Methods and Compositions for the Treatment of Proteinuric Diseases

ABSTRACT

The present invention is directed to methods of treating proteinuric diseases by the administration of avβ3 integrin inhibitors.

FEDERALLY SPONSORED RESEARCH

This invention was made with Government support under NIH grants DK073495, DK 057683, DK 062472 and George M. O'Brien kidney Centex DK064236. The Government has certain rights to this invention.

FIELD OF INVENTION

This invention relates generally to the treatment of proteinuricdiseases by αvβ3 integrin inhibitors.

BACKGROUND OF INVENTION

Urinary protein loss (proteinuria) affects some 100 million peopleworldwide and is a feature of kidney dysfunction of glomerular originand itself a risk factor for both renal and extra-renal diseases¹.Kidney podocytes and their foot processes (FP) are a key component ofthe ultrafiltration system in the glomerulus where they comprise thefiltration barrier together with endothelial cells and the glomerularbasement membrane (GBM). Podocytes are located within the glomerulus ofthe kidney where they are attached to the GBM via α3β1 integrin^(2, 3),and α/β dystroglycan⁴. Podocyte FPs are interconnected by the slitdiaphragm (SD), a modified adherens junction⁵. Proteinuric kidneydiseases are typically associated with various degrees of podocytemembrane remodeling (FP effacement and/or SD disruption) driven by arearrangement of the podocyte microfilament system⁶. Recent work hasadvanced our understanding of the molecular framework underlyingpodocyte structure largely through the analysis of hereditaryproteinuria syndromes and genetic models⁷. A few studies suggest alsomechanisms for the far more common acquired proteinuric diseases^(8, 9).Despite this progress, there are currently no cell-specific therapeuticsfor podocytes available. An emerging concept for the regulation ofpodocyte structure and function is the regulation of the podocytecytoskeleton by proteases such as cathepsin L^(8, 10). Cathepsin Linduction in podocytes is accompanied by an increase in cell motility ofcultured podocytes¹⁰. The increased motility of in vitropodocytes^(10, 11) is best translated into FP dynamics in vivo wherepodocytes remain locally attached to the GBM but may have altered FPdynamics resulting in FP fusion. In some forms of inflammatoryglomerular diseases such as crescentic glomerulonephritis, podocyteshave been reported to move out of their microenvironment into areas ofcrescentic glomerular damage¹². The concept of dynamic podocyte FPsdates far back into the 1970's where elegant studies of Seiler andcolleagues have shown that infusion of polycations such as protaminesulfate can induce rapid changes in FP dynamics and FP effacement¹³.Moreover, this event could be largely reversed by the infusion ofpolyanions such as heparin¹³. Even so it is impossible to image FPdynamics continuously in live animals, results from above studiessuggest a highly dynamic podocyte FP system. Moreover theelectron-microscopical analysis of normal kidney commonly reveals smallareas of FP effacement which probably represents FPs during transition.Cancer cell motility is another example where cells can be hyperdynamicor participate in tissue invasion¹⁴.

SUMMARY OF INVENTION

According to the invention methods for treating a proteinuric disorderare provided comprising administering to a patient in need thereof anavβ3 integrin inhibitor in an amount effective to reduce or eliminatethe proteinuric disorder. In one aspect of the invention the proteinuricdisorder is a kidney proteinuric disorder. In one aspect of theinvention the kidney proteinuric disorder is selected from a listcomprising of:

-   -   Diabetic nephropathy,    -   Nephrotic syndromes (i.e. intrinsic renal failure),    -   Nephritic syndromes,    -   Toxic lesions of kidneys,    -   Glomerular diseases, such as membranous glomerulonephritis,    -   Focal segmental glomerulosclerosis (FSGS),    -   IgA nephropathy (i.e., Berger's disease),    -   IgM nephropathy,    -   Membranoproliferative glomerulonephritis,    -   Membranous nephropathy,    -   Minimal change disease,    -   Hypertensive nephrosclerosis and

Interstitial nephritis.

In a certain embodiment of the invention the kidney proteinuric disorderis diabetic nephropathy.

In a certain other embodiment of the invention the kidney proteinuricdisorder is selected from to list comprising of:

-   -   Pre-eclampsia,    -   Eclampsia,    -   Collagen vascular diseases (e.g., systemic lupus erythematosus),    -   Dehydration,    -   Strenuous exercise,    -   Stress,    -   Benign Orthostatic (postural) proteinuria,    -   Sarcoidosis,    -   Alport's syndrome,    -   Diabetes mellitus,    -   Fabry's disease,    -   Infections (e.g., HIV, syphilis, hepatitis, post-streptococcal        infection),    -   Aminoaciduria,    -   Fanconi syndrome,    -   Heavy metal ingestion,    -   Sickle cell disease,    -   Hemoglobinuria,    -   Multiple myeloma,    -   Myoglobinuria,    -   Organ rejection,    -   Ebola hemorrhagic fever and    -   Nail Patella Syndrome.

In one aspect of the invention the abβ3 integrin inhibitor is a αvβ3monoclonal antibody or a peptide which contains a RGD binding sequence.In one aspect of the invention the avβ3 integrin inhibitor is a αvβ3monoclonal antibody. In one embodiment of the invention the αvβ3monoclonal antibody is anti-CD61.

In one embodiment of the invention the abβ3 integrin inhibitor is apeptide which contains a RGD binding sequence. In a certain embodimentof the invention the peptide which contains a RGD binding sequence iscyclo-[Arg-Gly-Asp-D-Phe-Val].

In one aspect of the invention the avβ3 integrin inhibitors is acompound of the formula:

or a pharmaceutically acceptable salt thereof.

In one aspect of the invention the avβ3 integrin inhibitors is selectedfrom the compounds described herein.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings are not intended to be drawn to scale. In thedrawings, each identical or nearly identical component that isillustrated in various figures is represented by a like numeral. Forpurposes of clarity, not every component may be labeled in everydrawing. In the drawings:

FIG. 1A-D is a panel of immunostaining images and a bar graph showinguPAR is induced in podocytes in proteinuric patients and experimentalproteinuric models.

-   -   (A) uPAR protein (green) is expressed in glomeruli of human        kidney. Some uPAR is found in podocytes as displayed by double        immunofluorescence with the podocyte marker synaptopodin (synpo,        red) resulting in a partial yellow overlap. (B) Induction of        glomerular uPAR mRNA in proteinuric patients. Quantitative        Real-time RT-PCR was performed on the isolated glomeruli from        human biopsies. Glomerular uPAR mRNA is upregulated in focal        segmental glomerulosclerosis (FSGS, n=14) and diabetic        nephropathy (DN, n=20). Values are presented as Mean±SEM.        *p<0.05 for FSGS or DN vs con (control patients). (C) Induction        of uPAR protein in podocytes in rodent models of proteinuria        revealed by immunocytochemistry. As shown by confocal        microscopy, uPAR expression (green) is low in control glomeruli        (con) from rat or mouse and colocalized partially with the        podocyte marker synaptopodin (synpo, red). In podocytes during        proteinuria (PAN, LPS, NZB/W F1), uPAR expression is        significantly induced in podocytes, resulting in a yellow        overlap with synaptopodin (merge). Original magnification, 600×.        Note that uPAR expression in New Zealand black/white (NZB/W) F1        mice (Lupus) appears more segmental within the glomerolus. (D)        Immunogold analysis of uPAR in glomerular walls of normal        (control) and 12 months old diabetic rats. uPAR expression is        found in all cells of the glomerulus including podocytes. uPAR        expression is significantly induced in foot processes of        diabetic rats. Original magnification, 35,000× Black arrows mark        uPAR expression in podocyte foot processes. MC=mesangial cell,        P=podocyte, End=endothelial cell, GBM=glomerular basement        membrane, US=urinary space, CL=capillary lumen.

FIG. 2A-H is a panel of immunostaining images and bar graphs showinguPAR is required in podocytes for the development of foot processeffacement and proteinuria.

-   -   (A) The morphology of podocyte foot processes is normal in PBS        injected wild type and uPAR^(-/-) mice. LPS treatment leads to        foot process effacement in wild type but not in uPAR^(-/-) mice.        Original magnification, 31700×. (B) Restoration of uPAR        expression in uPAR^(-/-) mice using transient gene transfer of        uPAR-cDNA leads to podocyte uPAR expression as shown by partial        overlap of uPAR with synaptopodin (merge). Original        magnification, 600×. (C) Immunoblot showing the amounts of        exogenous uPAR expressed in liver and glomeruli from uPAR^(-/-)        mice 14 h after gene delivery. (D) Gene delivery of uPAR-cDNA or        empty vector does not change the ultrastructure of podocyte foot        processes in uPAR^(-/-) mice. However, concomitant LPS treatment        leads to foot process effacement in uPAR-restored uPAR^(-/-)        mice, but not in UPAR^(-/-) mice given vector control. Original        magnification, 31700×. (E) Urine Bradford assay. Whereas PBS        treated control mice and uPAR^(-/-) mice do not have any        significant proteinuria, the injection of LPS induces        significant proteinuria in wild type mice (0.29±0.21 (wt con);        (0.82±0.32 (wt LPS), *p<0.003) but not in uPAR^(-/-) mice        (0.25±0.15 (uPAR^(-/-) con); (0.32±0.14 (uPAR^(-/-) LPS) or        uPAR^(-/-) mice which received control plasmids (0.14±0.06        (uPAR^(-/-) con); (0.26±0.15 (uPAR^(-/-) LPS). These data        indicate that uPAR^(-/-) mice were protected from urinary        protein loss. uPAR^(-/-) mice reconstituted with uPAR-cDNA        develop heavy proteinuria but like wild type mice only after LPS        injection (0.11±0.11 (uPAR^(-/-) uPAR-cDNA); (0.92±0.46        (uPAR^(-/-) uPAR-cDNA LPS), *p<0.002). The degree of proteinuria        was comparable in LPS treated wild type and uPAR-cDNA        reconstituted uPAR^(-/-) mice, n=15 for each group.    -   (F) Podocyte-uPAR expression in uPAR^(-/-) mice is achieved by        gene transfer of podocin-driven uPAR cDNA (Pod-uPAR) and        monitored by synaptopodin staining. Note the merge of uPAR and        synaptopodin labeling (merge).    -   (G) Endothelial-uPAR expression in uPAR^(-/-) mice achieved by        gene transfer of ICAM-2-driven uPAR cDNA (ICAM-2-uPAR) is        monitored by staining with the endothelial marker CD31. Note the        merge of uPAR and CD31 labeling (merge).    -   (H) Fold-change in urinary protein loss in uPAR^(-/-) mice        following gene-transfer of Podocin-uPAR or ICAM-2-uPAR with and        without LPS treatment.

FIG. 3A-D is a panel of immunostaining images and bar graphs showinguPAR mediates podocyte migration.

-   -   (A) Multiwell Boyden chamber assay on vitronectin-coated surface        under normal conditions and in the presence of LPS or PAN.        Podocytes, which migrated randomly through the membrane, were        stained with DAPI (blue). (B) When compared to control, LPS and        PAN treatment for 24 h promoted podocyte migration (wild type        41±3.7; LPS 72±5.5; PAN 67±4.9). Wild type: *P<0.001 for LPS vs        control; *p<0.002 for PAN vs control. Knockdown of uPAR by siRNA        strongly reduced podocyte migration in comparison with wild type        podocytes under normal conditions and after treatment with LPS        or PAN (uPAR-siRNA 16±2.4); (uPAR-siRNA LPS 12±3.6; uPAR-siRNA        PAN 15±2.9). Wild type vs uPAR-siRNA *p<0.001. (C-D) Scrape        wound assay on vitronectin-coated surface to assess directed        podocyte motility. 24 h after scraping, wild type podocytes        started to move into the wound track (61.37±8.05). The treatment        with LPS (85.34±4.1) or with PAN (79.31±3.72) for 24 h        significantly enhanced directed podocyte motility (*p<0.015 for        LPS vs control); (*p<0.025 for PAN vs control). uPAR-siRNA        expressing podocytes displayed defects in directed motility        (uPAR-siRNA 17.24±10.48); (uPAR-siRNA LPS 28.00±7.17);        (uPAR-siRNA PAN 22.26±6.92). Compared to wild type podocytes,        uPAR-siRNA showed decreased capability to migrate into the wound        track within 24 hours (*p<0.00241 for wild type vs uPAR-siRNA).        Solid red lines indicate the initial margins of scrape wound.        Data were based on six independent experiments. Original        magnification, 40×.

FIG. 4A-C is a panel of a scheme, immunostaining image and bar graphshowing uPAR, β3 integrin and vitronectin are important for LPS inducedproteinuria.

-   -   (A) Schematic depiction of uPAR in complex with avβ3 integrin        and vitronectin. Domain 2 of uPAR has been shown to interact        with avβ3 integrin but other domains of uPAR may also        contribute. The association of uPAR with avβ3 integrin can lead        to conformational changes of the integrin consistent with        activation that facilitates binding to ligands such as        vitronectin. (B) Immunogold analysis of uPAR and β3 integrin in        podocyte foot processes shows similarities in their distribution        pattern. Both uPAR and β3 integrin are often located in vicinity        to the slit diaphragm (black arrows). (C) The absence of uPAR        (see FIG. 2E), β3 integrin (β3) and vitronection (Vn) is        associated with normal renal permselective function and lack of        proteinuria after LPS stimulation. In contrast, mice deficient        in urokinase (uPA) have no proteinuria under normal conditions,        but readily develop urinary protein loss after LPS        administration. The same is observed for LPS treated uPAR^(-/-)        mice after gene delivery of UPAR-cDNA (uPAR-WT) or of an        uPAR-cDNA encoding for a uPAR which is deficient in binding a3β1        integrin (uPAR-D262A).

FIG. 5A-E is a panel of immunostaining images and a bar graph showinguPAR activates β3 integrin.

-   -   (A) Double-immunofluoresence staining for β3 integrin (green)        and the podocyte marker synaptopodin (synpo, red) in glomeruli        from wild typo and uPAR^(-/-) mice before and after treatment        with LPS using confocal microscopy (original magnification,        600×). LPS treatment does not change podocyte β3 integrin in        wild type and uPAR^(-/-) mice. (B) Flow cytometry of AP5 in LPS        treated podocytes in the presence of various amounts of Ca²⁺.        Fluorescent intensity units: EDTA: 3020.64±302.06; 0.1 mM Ca⁺⁺:        3055.76±400; 0.4 nM Ca⁺⁺: 1644.7±200; 1.0 mM Ca⁺⁺: 534.52±121;        2.0 mM Ca⁺⁺: 312.5±53.45. (C) same as (A) but now with the        antibody AP5 which recognizes active β3 integrin. LPS treatment        induces staining for AP5 in wild type but not in uPAR^(-/-)        mice. (D) Immunofluorescent analysis and confocal microscopy of        AP5 labeling (red) and uPAR (green) in uPAR downregulated        podocytes using siRNA, in control podocytes and in podocytes        overexpressing GFP-uPAR. (E) Activity assay of the small GTPases        cdc42 and Rac1 isolated glomeruli form wild type and uPAR^(-/-)        mice before and after treatment with LPS. In some experiments,        wild type mice were treated with LPS and Cyclo-RGDfV which        blocks αvβ3 integrin.

FIG. 6A-G is A panel of immnunostaining images and bar graphs showingthe active uPAR-αvβ3 integrin complex is lipid dependent and can betargeted pharmacologically to modify proteinuria.

-   -   (A) Sucrose gradient differential centrifugation was performed        on podocyte whole cell extracts of normal and LPS treated cells.        Each fraction was separated and blotted with raft        (anti-caveolin) and non-rafts marker (anti-transferrin        receptor), as well as anti-uPAR and anti-β3 integrin. Under        normal conditions, uPAR and β3 integrin are preferentially        associated with non-rafts fractions. Both, uPAR and β3 integrin        are enriched within the lipid raft fraction after LPS        treatment. (B) Localization of uPAR and active β3 integrin        (AP5-labeling) in podocytes before and after LPS treatment and        in the presence of the cholesterol depleting agent        Methyl-β-cyclodextrine (MBCD). (C) Immunofluorescent staining of        active β3 integrin in glomeruli of uPAR^(-/-) mice (con) and of        uPAR^(-/-) mice which received β3 integrin cDNA (β3 integrin)        and a cDNA encoding for the β3 integrin with a deletion of        aminoacids 616-690 (β3Δ₆₁₆₋₆₉₀). The latter confers constitutive        activity to β3 integrin which is heavily stained by WOW-1 Fab        antibody. (D) Gene transfer of cDNA encoding for the        constitutively active β3 integrin but not the gene transfer of a        cDNA coding for normal β3 integrin is sufficient to cause        proteinuria in uPAR^(-/-) mice even in the absence of LPS (con        0.25±0.06); (β3 integrin 0.19±0.05); (β3Δ₆₁₉₋₆₉₀ integrin        0.43±0.09). *P<0.01 for β3 vs β3Δ₆₁₆₋₆₉₀ integrin, injected        mice, n=6 for each group. (E) Co-injection of LPS and a β3        integrin blocking antibody (anti-CD61) in wild type mice        prevents the development of proteinuria (PBS con 0.12±0.03);        (LPS+IgG con 0.84±0.14); (LPS+anti-β3 integrin 0.13±0.01).        *p<0.001 for LPS+anti-β3 integrin vs IgG con. n=6. (F)        Co-administration of LPS and anti-CD61 (anti-β3 integrin)        antibody to cultured podocytes reduces podocyte motility        (LPS+IgG con 88.56±7.26); (LPS+anti-β3 integrin 54.53±10.15).        *p<0.03 for LPS+anti-β3 integrin vs IgG con. (G) The injection        of cyclo-[Arg-Gly-Asp-D-Phe-Val] RGDfV blocks αvβ3 integrin and        significantly reduces the degree of proteinuria in LPS treated        mice. The injection of RGDfV reduces proteinuria in a dose        dependent manner (Con, 0.2064±0.038; cyclo-RGDfV, 0.28±0.0535;        LPS, 0.924±0.1055; LPS+cyclo-RGDfV (1 mg), 0.712±0.0817;        LPS+cyclo-RGDfV (5 mg), 0.5683±0.0729; LPS+cyclo-RGDfV (20 mg),        0.4172±0.0423. *p<0.013 for LPS vs LPS+cyclo-RGD).

FIG. 7A-C is a panel of a scheme, immunostaining images and a bar graphshowing induction of uPAR in cultured podocyte in response to LPS andPAN.

-   -   (A) Schematic representing of a kidney glomerulus and the        glomerular filtration barrier. (B) Induction of uPAR in cultured        podocyte in response to LPS and PAN. Relative quantification of        uPAR induction: Con: 0.31±0.06; LPS: 0.49±0.06: PAN: 0.61±0.10.        *P<0.025 for Con vs LPS and *P<0.015 for Con vs PAN. (C) Induced        uPAR in podocytes localizes preferentially to the leading edge        of migrating podocytes, arrows indicate plasma membrane        localization.

FIG. 8A-B is a panel of immunostaining images showing Vitronectin isexpressed in the human glomerulus and mainly in podocytes.

-   -   (A) Vitronectin (green) is expressed in the human glomerulus and        mainly in podocytes, as displayed by double immunofluorescence        with the podocyte marker synaptopodin (synpo, red) resulting in        a partial yellow overlap. Podocytes are able to produce        vitronectin as tested by RT-PCR. The vitronectin primers are as        follows:

Forward: 5′ AGT GGA GCA ACA GGA GGA GA 3′

Reverse: 5′ CAA GGC AAA GTG CTC AAA CA 3′ (data not shown). (B)Induction of vitronectin in podocytes in rodent models of proteinuriarevealed by immunocytochemistry. As shown by confocal microscopy,vitronectin expression (green) is low in control glomeruli (con) fromrat or mouse and colocalized partially with the podocyte markersynaptopodin (synpo, red). In nephrotic conditions however (PAN, LPS,NZB/W F1), vitronectin expression is significantly induced in podocytes,resulting in a yellow overlap with synaptopodin (merge). Originalmagnification, 600×. Note that vitronectin expression in New Zealandblack/white (NZB/W) F1 mice (model for Lupus glomerulonephritis) appearsmore segmental within the glomerulus.

FIG. 9A-D is a panel of immunostaining images and graphs showing stableknockdown of uPAR mRNA using siRNA.

-   -   (A) Stable knockdown of uPAR mRNA using siRNA. (B) Decreased        uPAR protein levels in uPAR siRNA expressing podocytes. (C)        Time-course of wound closure in cultured podocytes. The distance        migrated by cells from the wound margin was related to the width        of the scar at different time points. (D) The addition of        urokinase (uPA) to cultured podocytes did not modify podocyte        motility.

FIG. 10A-B is a panel of immunostaining images showing uPAR interactswith β3 integrin.

-   -   (A) Heterogeneous Co-IP was performed on the lysates of HEK        cells co-transfected with uPAR and β3 integrin, and blotted with        HA or Flag antibodies. The results show that uPAR interacts with        β3 integrin. (B) Heterogeneous Co-IP was performed on the        lysates of HEK cells co-transfected with mouse β1integrin and        full length human uPAR or an uPAR cDNA (uPAR D262A) deficient in        the binding of β1 integrin. After blotting with HA or Flag        antibodies the results show that full length human uPAR but not        uPAR D262A interacts with mouse β1 integrin.

FIG. 11 is a bar graph showing the effect of cyclo-RGDfV on recovery ofproteinuria.

DETAILED DESCRIPTION

The present invention is directed to methods of treating proteinuricdiseases by the administration of avβ3 integrin inhibitors. Theinvention is based at least in part on the discovery that induction ofurokinase receptor signaling in podocytes leads to foot processeffacement and urinary protein loss via a mechanism including lipiddependent activation of avβ3 integrin.

The invention involves, at least in part, the study of molectdes whichare associated with cellular motility such as the urokinase plasminogenactivator receptor (uPAR)^(15, 16). uPAR is aglycosylphosphatidylinositol (GPI)-anchored protein that has beenrecognized as a proteinase receptor but has also be involved innon-proteolytic pathways, mainly through its ability to form complexeswith other membrane proteins such as integrins for signaltransduction¹⁵. uPAR plays important roles during wound healing,inflammation, and stem cell mobilization, as well as in severepathological conditions such as HIV-1 infection, tumor invasion andmetastasis¹⁷. Besides uPAR's well-established role in the regulation ofpericellular proteolysis, it is also involved in cell adhesion,migration, and proliferation through interactions with proteins presentin the extracellular matrix, including vitronectin (Vn)¹⁸. Mostrecently, the importance of uPAR-Vn interactions was demonstrated by thedirect requirement of uPAR to bind Vn for the sufficient induction ofdownstream signaling aimed at cell motility and morphology¹⁹.

Although not wishing to be bound by theory the invention is based on theexperimental observations discussed herein that present a mechanism thatinvolves activation of avβ3 integrin within lipid rafts²⁴. Theinhibition of uPAR/avβ3 integrin function in podocytes ameliorated thecourse of proteinuria and opens novel avenues for pharmacologicalinterventions. Blockade of avβ3 integrin reduces podocyte motility invitro and proteinuria in mice. Mice deficient of uPAR are protected fromproteinuria unless a constitutively active β3 integrin is expressed.Gene transfer of uPAR into podocytes but not into endothelial cellsconferred the ability to develop urinary protein loss. Mechanistically,uPAR may be required to activate avβ3 integrin in podocytes whichpromotes cell motility and activation of small GTPases cdc42 and Rac1.There is induction of uPAR expression in podocytes during human androdent proteinuric kidney diseases. uPAR is required for podocytemigration and LPS-induced FP effacement and proteinuria in mice via amechanism that includes lipid-dependent activation of αvβ3 integrin.These findings define a novel signaling pathway in podocytes whichinvolves uPAR, αvβ3 integrin and Vn. The examples also describe amechanism whereby widely expressed proteins such as uPAR are utilized incell-specific manner to regulate basic mechanisms such as kidneyfiltration. uPAR expression is present in all glomerular cells, yet uPARexpression is not required for normal renal function in any of the cellsas the uPAR^(-/-) mice behave normal. Surprising is the requirement ofuPAR during the development of podocyte FP effacement and proteinuriawhich suggests that inducible pathways are required for the remodelingof the filtration barrier. uPAR action for the development ofproteinuria stems from its action in the podocyte, which wasdemonstrated using cell-specific promoter elements. In one aspect of theinvention methods for treating proteinuria are provided by inhibitingavβ3 integrin function by inhibiting uPAR function. uPAR is inducedduring proteinuria and that uPAR-/- mice are protected from thedevelopment of proteinurea. In one aspect of the invention the uPARinhibitors, including small molecules, peptides and antibodies can beused to inhibit avβ3 integtin function.

Accordingly, the methods of the present invention are used to treatdisorders characterized by proteinuria. As used herein “proteinuria”refers to any amount of protein passing through a podocyte, such as apodocyte that has suffered podocyte damage. For example, the processingof protein by cultured podocytes that have undergone actin-cytoskeletonrearrangment and FP effacement would result in proteinuria. As usedherein “podocyte damage” refers to FP effacement and/or cortical actinrearrangement or any other reversible structural or functional change inpodocytes that results in proteinuria. In an in vivo system the term“proteinuria” refers to the presence of excessive amounts of serumprotein in the urine. In a certain embodiment the excessive amount ofserum protein in the urine is greater than 50, 100, 150, or 200 mg ofserum protein/day. In a preferred embodiment the amount of serum proteinin the urine is greater than 150 mg/day. Proteinuria is a characteristicsymptom of either renal (kidney), urinary, pancreatic distress,nephrotic syndromes (for example, proteinuria larger than 3.5 grams perday), eclampsia, toxic lesions of kidneys, and it is frequently asymptom of diabetes mellitus. With severe proteinuria generalhypoproteinemia can develop and it results in diminished oncoticpressure (ascites, edema, hydrothorax).

As used herein a proteinuric disorder refers to, but it is not limitedto: Diabetic nephropathy, Nephrotic syndromes (i.e. intrinsic renalfailure), Nephritic syndromes, Toxic lesions of kidneys, Glomerulardiseases, such as membranous glomerulonephritis, Focal segmentalglomerulosclerosis (FSGS), IgA nephropathy (i.e., Berger's disease), IgMnephropathy, Membranoproliferative glomerulonephritis, Membranousnephropathy, Minimal change disease, Hypertensive nephrosclerosis andInterstitial nephritis.

In certain embodiments as used herein, a proteinuric disorder refers to:Pre-eclampsia, Eclampsia, Collagen vascular diseases (e.g., systemiclupus erythematosus), Dehydration, Strenuous exercise, Stress, BenignOrthostatic (postural) proteinuria, Sarcoidosis, Alport's syndrome,Diabetes mellitus, Fabry's disease, Infections (e.g., HIV, syphilis,hepatitis, post-streptococcal infection), Aminoaciduria, Fanconisyndrome, Heavy metal ingestion, Sickle cell disease, Hemoglobinuria,Multiple myeloma, Myoglobinuria, Organ rejection, Ebola hemorrhagicfever and Nail Patella Syndrome.

In certain embodiments as used herein a proteinuric disorder refers todiabetes, hypertension, kidney disease, minimal change disease,membranous glomerulonephritis, focal segmental glomerulosclerosis,diabetic neuropathy, post-infectious glomerulonephritis,mesangioproliferative glomerulonephritis, HIV-associated nephropathy,IgA-nephropathy, and Cardiovascular disease.

At the cellular level protein loss in the urine is accompanied by astructural re-arrangement of podocyte cells. Renal ultrafiltration islocated within the renal glomerulus, a combination of blood vessels andcells. Highly specialized podocyte cells perform the filtering work andare main target cells in kidney disease. Podocytes can reorganize theiractin-based cytoskeleton in a highly dynamic fashion. Such areorganization determines the integrity of the ultrafiltration barrierin the kidney. Reorganization of the actin cytoskeleton in podocyte footprocesses from stress fibers into cortical actin leads to podocyte footprocesses (FP) effacement and the development of urinary protein loss.Podocyte damage can be caused by many conditions and factors includingLPS and purine aminonucleoside (PAN). These alterations lead to ongoingdamage of the kidney and over time to a deterioration of the kidneyfunction. The instant invention is based in part on the surprisingdiscovery of the functional significance of αvβ3 integrin activation asa downstream effector for increased podocyte motility and FP effacement.

Integrins belong to the family of heterodimeric class I transmembranereceptors, which play an important role in numerous cell-matrix andcell-cell adhesion processes (Tuckwell et al., 1996, Symp. Soc. Exp.Biol. 47). They can be divided roughly into three classes: the β1integrins, which are receptors for the extracellular matrix, the β2integrins, which can be activated on leucocytes and are triggered duringinflammatory processes, and the αv integrins, which influence the cellresponse in wound-healing and other pathological processes (Marshall andHart, 1996, Semin. Cancer Biol. 7, 191).

The αbβ3 integrin, also called that the vitronectin receptor, mediatesadhesion to a multiplicity of ligand's-plasma proteins, extracellularmatrix proteins, cell surface proteins, of which the majority containthe amino acid sequence Arg-Gly-Asp (RGD), such as, for example,fibronectin or vitronectin. Soluble RGD-containing peptides are capableof inhibiting the interaction of each of these integrins with thecorresponding natural ligands. Integrin αvβ3 antagonistic action hasbeen shown for a multiplicity of compounds, such as anti-αvβ3 monoclonalantibodies, peptides which contain the RGD binding sequence, natural,RGD-containing proteins (e.g. disintegrins) and low-molecular weightcompounds, (FEBS Letts 1991, 291, 50-54; J. Biol. Chem, 1990, 265,12267-12271; J. Biol. Chem. 1994, 269, 20233-20238; J. Cell Biol 1993,51, 206-218; J. Biol. Chem. 1987, 262, 17703-17711; Bioorg. Med. Chem.1998, 6, 1185-1208).

Advantageous αvβ3 integrin receptor ligands bind to the integrin αvβ3receptor with an increased affinity by at least a factor of 10,preferably at least a factor of 100.

In one aspect of the invention a method for treating a proteinuricdisorder comprising administering to a patient in need thereof an αvβ3integrin inhibitors is provided. According to one embodiment of theinvention the αvβ3 integrin inhibitors are the compounds described in WO97/08145 A1, WO 00/48996 A2, WO 06043930 A1, US2002072500, US2005043344, US 2002045645, US 2002099209, US 2005020505, US 2002072518,US 2002077321, US 2004043994, US 2003069236, US 2003144311.

In one embodiment of the invention the αvβ3 integrin inhibitors arepeptidic sulfonamides having the formula (I):R¹-Arg-X-Asp-Leu-Asp-Ser-Leu-Arg-R², in which R¹ denotes H, acetyl oracyl and R² denotes —Oh, OR³N₂,NHR³, N(R³)₂ R³ denotes alkyl, aralkyl,aryl, Het and X denotes an amino acid, in which A denotes (CH₂)_(n) R⁴denotes H, alkyl, aralkyl or aryl, and n denotes 1, 2, 3, 4, 5 or 6, andthe amino acid is bonded to the adjacent Arg via a peptide bond of theα-amino group and to the α-amino group of the adjacent Asp via a peptidebond of the α-carboxyl group as described in U.S. patent application No.2006/0148716 A1.

In one embodiment of the invention the αvβ3 integrin inhibitors arefluoro-alkyl-cyclopeptide derivatives as described in WO 2004/011487 A2.

In one embodiment of the invention the αvβ3 integrin inhibitors arepeptido-mimetic compounds containing an RGD sequence as described in WO2005/007654 A1 and U.S. Pat. No. 6,451,972.

In one embodiment of the invention the αvβ3 integrin inhibitors areantagonists of the αvβ3 integrin receptor based on a bicyclic structuralelement are described in WO 9906049, WO 9905107, WO 9814192, WO 9724124,WO 9724122 and WO 9626190.

In one embodiment of the invention the αvβ3 integrin inhibitors arecompounds to described in U.S. Publication No 2004/0063934.

The αvβ3 integrin inhibitors of the invention include isolated peptidesand proteins. As used herein with respect to polypeptides, proteins orfragments thereof, “isolated” means separated from its nativeenvironment and present in sufficient quantity to permit itsidentification or use. Isolated, when referring to a protein orpolypeptide, means, for example: (i) selectively produced by expressioncloning or (ii) purified as by chromatography or electrophoresis.Isolated proteins or polypeptides may be, but need not be, substantiallypure. The term “substantially pure” means that the proteins orpolypeptides are essentially free of other substances with which theymay be found in nature or in vivo systems to an extent practical andappropriate for their intended use. Substantially pure polypeptides maybe produced by techniques well known in the art. Because an isolatedprotein may be admixed with a pharmaceutically acceptable carrier in apharmaceutical preparation, the protein may comprise only a smallpercentage by weight of the preparation. The protein is nonethelessisolated in that it has been separated from the substances with which itmay be associated in living systems, i.e. isolated from other proteins.

The αvβ3 integrin inhibitors of the invention may be produced using anyof the methods and techniques known to those skilled in the art. Forexample, αvβ3 integrin inhibitors can be purified from a source whichnaturally expresses the protein, can be isolated fman a recombinant hostwhich has been altered to express the desired mutant or fragmentthereof, or can be synthesized using protein synthesis techniques knownin the art. The skilled artisan can readily adapt a variety oftechniques in order to obtain αbβ3 integrin inhibitors that arepeptides, proteins or fragments thereof.

Other agents that are αvβ3 integrin inhibitors include but are notlimited to small molecules, and other drugs, including known drugs, thatprevent (i.e. reduce or inhibit further increase) integrin activation.Such agents can be identified using routine screening methods. Forinstance, αvβ3 integrin inhibitors of the present invention can beidentified using the methods and assays described herein. The screeningmay be a random screen or it may be rationally designed. For randomscreening, putative inhibitors are selected at random and assayed fortheir ability to produce the desired physiological effect. For instance,the putative modulators may be assayed for the ability to reduceselectively or specifically the amount or rate of αvβ3 integrinactivation. Any suitable method or technique known to those skilled inthe art may be employed to assay putative inhibitors.

Methods for screening using rational design employ the same types ofscreening methods but begin with a set of compounds that has beendesigned to specifically maximize function. For rational selection ordesign, the αvβ3 integrin inhibitors may be selected based, for exampleon the RGD binding domain. Any of the suitable methods and techniquesknown to those skilled in the art may be employed for rational selectionor design. For example, one skilled in the art can readily adaptcurrently available procedures to generate pharmaceutical agents capableof binding to a specific peptide sequence of αbβ3 integrin or uPAR,precluding their interaction and signal transduction and therebyinhibiting αvβ3 integrin activity. Illustrative examples of suchavailable procedures are described, for example, in Hurby et al.,“Application of Synthetic Peptides: Antisense Peptides,” in SyntheticPeptides, A User's Guide, W. H. Freeman, N.Y., pp. 289-307 (1992);Kaspczak et al., Biochemistry 28:9230 (1989); and Harlow, Antibodies,Cold Spring Harbor Press, N.Y. (1990).

In one aspect of the invention αvβ3 integrin inhibitors includeantibodies and antibody fragments which are capable of binding to αvβ3integrin and consequently acting as a αvβ3 integrin inhibitors. Theantibodies of the present invention include polyclonal and monoclonalantibodies, as well as antibody fragments and derivatives that containthe relevant antigen binding domain of the antibodies. Such antibodiesor antibody fragments are preferably used in the diagnostic andtherapeutic embodiments of the present invention. In a preferredembodiment the antibody is anti-CD61 antibody.

As used herein, “treating a proteinuric disorder” includes preventingthe development of proteinurea, reducing or inhibiting proteinurea,slowing the progression, and/or any other desired effect on proteinurea.According to the invention the αvβ3 integrin inhibitors can beadministered prior to the onset of proteinurea, following the onset ofproteinurea, or as part of any therapeutic regimen, for example,including cancer medicaments.

The methods of the invention are intended to embrace the use of morethan one other medicament along with the αvβ3 integrin inhibitor. As anexample, where appropriate, the αvβ3 integrin inhibitor may beadministered with both a chemotherapeutic agent, anti-diabetic agent oran immunotherapeutic agent.

The invention also encompasses diagnostic assays for determining thepresence of a disorder characterized by proteinuria in a subject. Thisaspect of the invention is based, at least in part, on the discoverythat αvβ3 integrin activation is reduced in damaged or proteinuricpodocytes. In the method an amount of αvβ3 integrin activity in apodocyte cell is determined. That amount is compared to a pre-determinedthreshold or to a control level. A disorder characterized by proteinuriais determined when the amount of αvβ3 integrin activity is below thepre-determined threshold. As used here in “pre-determined threshold or acontrol level” refers to αvβ3 integrin activity levels in normal,healthy podocytes, i.e. podocytes not affected by podocyte damage orproteinuria. The podocyte cells may be within a biological sample. Thebiological sample may be, for instance, a biopsy sample of proteinurictissue. As used herein, activity refers to expression and well asbiochemical activity as described herein.

The detection of αvβ3 integrin in podocyte cells can be readily carriedout by standard immunostaining or immunocytometric methods, readilyknown by persons of ordinary skill in the art. As used herein“immunostaining” refers to a technique of applying coloured orfluorescent dyes to tissues in preparation for microscopic examination.The assay may be performed using immunogold election microscopy.

In one embodiment the diagnostic assays are performed on cells and/ortissue samples wherein morphological changes of the actin-cytoskeletoncan not be readily detected by any other immunocytometric methods. Forexample one such disorder would be minimal change disease. The termminimal change disease comes from the notion that morphological podocytechanges are only visible by electron microscopy. Detection ofproteinuria in patients with minimal change disease by immunocytometricmethods would be advantageous because it provide ease and speed ofdetection.

The immunocytometric methods may be performed using labeled antibodies.An antibody is said to be “detectably labeled” if the antibody, orfragment thereof, is attached to a molecule which is capable ofidentification, visualization, or localization using known methods.Suitable detectable labels include radioisotopic labels, enzyme labels,non-radioactive isotopic labels, fluorescent labels, affinity labels,chemiluminescent labels and nuclear magnetic resonance contrast agents.

Illustrative examples of suitable enzyme labels include, but are notlimited to, luciferase, malate dehydrogenase, staphyloccal nuclease,delta-5-steroid isomerase, yeast-alcohol dehydrogenase, alpha-glycerolphosphate dehydrogenase, triose phosphate isomerase, horseradishperoxidase, alkaline phosphatase, asparaginase, glucose, oxidase,beta-galactosidase, ribonuclease, urease, catalase, glucose-6-phosphatedehydrogenase, glucoamylase, and acetylcholine esterase.

Examples of suitable radioisotopic labels include, but are not limitedto, ³H, ¹¹¹In, ¹²⁵I, ¹³¹I, ³²P, ³⁵S, ¹⁴C, ⁵¹Cr, ⁵⁷To, ⁵⁸Co, ⁵⁹Fe, ⁷⁵Se,¹⁵²Eu, ⁹⁰Y, ⁶⁷Cu, ²¹⁷Ci, ²¹¹At, ²¹²Pb, ⁴⁷Sc, ¹⁰⁹Pd, etc. ¹¹¹In is apreferred isotope where in vivo imaging is used since its avoids theproblem of dehalogenation of the ¹²⁵I or ¹³¹I-labeled monoclonalantibody by the liver. In addition, this radionucleotide has a morefavorable gamma emission energy for imaging (Perkins et al., Eur. J.Nucl. Med 10:296-301 (1985); Carasquillo et al., J. Nucl. Med.28:281-287 (1987)). For exaample ¹¹¹In coupled to monoclonal antibodieswith 1-(p-isothiocyanatobenzyl)-DPTA has shown little uptakenon-tumorous tissues, particularly the liver, and therefore enhancesspecificity of tumor localization (Esteban et al., J. Nucl. Med.28:861870 (1987)).

Illustrative examples of suitable non-radioactive isotopic labelsinclude, but are not limited to, ¹⁵⁷Gd, ⁵⁵Mn, ¹⁶²Dy, ⁵²Tr, and ⁵⁶Fe.

Illustrative examples of suitable fluorescent labels include, but arenot limited to, an ¹⁵²Eu label, a fluorescent protein (including greenfluorescent protein (GFP), enhanced green fluorescent protein (EGFP),enhanced yellow fluorescent protein (YFP) and enhanced cyan fluorescentprotein (ECFP),), a fluorescein label, an isothiocyanate label, arhodamine label, a phycoerythrin label, a phycocyanin label, anallophycocyanin label, an o-phthaldehyde label, and a fluorescaminelabel.

Illustrative examples of chemiluminescent labels include a luminallabel, an isoluminal label, an aromatic acridinium ester label, animidazole label, an acridinium salt label, an oxalate ester label, aluciferin label, a luciferase label, and an aequorin label.

Illustrative examples of nuclear magnetic resonance contrasting agentsinclude paramagnetic heavy metal nuclei such as Gd, Mn, and Fe.

The coupling of one or more molecules to antibodies is envisioned toinclude many chemical mechanisms, for instance covalent binding,affinity binding, intercalation, coordinate binding, and complexation.

The covalent binding can be achieved either by direct condensation ofexisting side chains or by the incorporation of external bridgingmolecules. Many bivalent or polyvalent agents are useful in couplingprotein molecules to other proteins, peptides or amine functions, etc.For example, the literature is replete with coupling agents such ascarbodiimides, diisocyanate, glutaraldehyde, diazobenzenes, andhexamethylene diamines. This list is not intended to be exhaustive ofthe various coupling agents known in the art but, rather, is exemplaryof the more common coupling agents.

According to the methods of the invention the αvβ3 integrin inhibitorsare administered in pharmaceutically acceptable preparations. Whenadministered, the pharmaceutical preparations of the invention areapplied in pharmaceutically-acceptable amounts and inpharmaceutically-acceptable compositions. The term “pharmaceuticallyacceptable” means a non-toxic material that does not interfere with theeffectiveness of the biological activity of the active ingredients. Suchpreparations may routinely contain salts, buffering agents,preservatives, compatible carriers, and optionally other therapeuticagents. When used in medicine, the salts should be pharmaceuticallyacceptable, but non-pharmaceutically acceptable salts may convenientlybe used to prepare pharmaceutically-aceeptable salts thereof and are notexcluded from the scope of the invention.

As used herein, “pharmaceutically acceptable carrier” or“physiologically acceptable carrier” includes any and all salts,solvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like that arephysiologically compatible. Preferably, the carrier is suitable forintravenous, intramuscular, subcutaneous, parenteral, per os, spinal orepidermal administration (e.g., by injection or infusion). Depending onthe route of administration, the active compound, i.e., αvβ3 integrininhibitor may be coated in a material to protect the compound from theaction of acids and other natural conditions that may inactivate thecompound. Preferably the carrier is sterile.

A salt retains the desired biological activity of the parent compoundand does not impart any undesired toxicological effects (see e.g.,Berge. S. M., et al. (1977) J. Pharm. Sci, 66: 1-19). Examples of suchsalts include acid addition salts and base addition salts. Acid additionsalts include those derived from nontoxic inorganic acids, such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic,phosphorous and the like, as well as from nontoxic organic acids such asaliphatic mono- and dicarboxylic acids, phenyl substituted alkanoicacids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromaticsulfouic acids and the like. Base addition salts include those derivedfrom alkaline earth metals, such as sodium, potassium, magnesium,calcium and the like, as well as from nontoxic organic amines, such asN,N′-dibenzylethylenediamine N-methylglocamine, chioroprocaine, choline,diethanolamine, ethylenediamine, procaine and the like.

The pharmaceutical compositions may contain suitable buffering agent,including: acetic acid in a salt; citric acid in a salt; boric acid in asalt; and phosphoric acid in a salt. The pharmaceutical compositionsalso may contain, optionally, suitable preservatives, such as:benzalkonium chloride; chlorobutanol; parabens and thimerosal.

The pharmaceutical compositions may conveniently be presented in unitdosage form and may be prepared by any of the methods well-known in theart of pharmacy. All methods include the step of bringing the activeagent into association with a carrier which constitutes one or moreaccessory ingredients. In general, the compositions are prepared byuniformly and intimately bringing the active compound into associationwith a liquid carrier, a finely divided solid carrier, or both, andthen, if necessary, shaping the product.

Compositions suitable for parenteral administration convenientlycomprise a sterile aqueous or non-aqueous preparation of the compounds,which is preferably isotonic with the blood of the recipient. Thispreparation may be formulated according to known methods using suitabledispersing or wetting agents and suspending agents. The sterileinjectable preparation also may be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water. Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono-ordi-glycerides. In addidon, fatty acids such as oleic acid may be used inthe preparation of injectables. Carrier formulations suitable for oral,subcutaneous, intravenous, intramuscular, etc. administration can befound in Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton, Pa.

The active compounds can be prepared with carriers that will protect thecompound against rapid release, such as a controlled releasefornaulation, including implants, transdermal patches, andmicroencapsulated delivery systems. Biodegradable, biocompatiblepolymers can be used, such as ethylene vinyl acetate, polyanhydrides,polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Manymethods for the preparation of such formulations are patented orgenerally known to those skilled in the art. See, e.g., Sustained andControlled Release Drug Delivery Systems, J. R. Robinson, ed., MarcelDekker, Inc., New York, 1978.

The present invention therefore provides pharmaceutical compositionscomprising one or more αvβ3 integrin inhibitors. These pharmaceuticalcompositions may be administered orally, rectally, parenterally,intrathecally, intracisternally, intravaginally, intraperitoneally,topically (as by powders, ointments, drops or transdermal patch),bucally, or as an oral or nasal spray. The term “parenteral” as usedherein refers to modes of administration which include intravenous,intramuscular, intrathecal, intraperitoneal, intrasternal, subcutaneousand intraarticular injection and infusion. One of ordinary skill willrecognize that the choice of a particular mode of administration can bemade empirically based upon considerations such as the particulardisease state being treated; the type and degree of the response to beachieved; the specific agent or composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration and rate of excretion of the agent or composition; theduration of the treatment; drugs used in combination or coincidentalwith the specific composition; and like factors well known in themedical arts.

Pharmaceutical compositions of the present invention for parenteralinjection may comprise pharmaceutically acceptable sterile aqueous ornonaqueous solutions, dispersions, suspensions or emulsions as well assterile powders for reconstitution into sterile injectable solutions ordispersions just prior to use. Illustrative examples of suitable aqueousand nonaqueous carriurs, diluents, solvents or vehicles include, but arenot limited to, water, ethanol, polyols (such as glycerol, propyleneglycol, polyethylene glycol, and the like), carboxymethylceuulose andsuitable mixtures thereof, vegetable oils (such as olive oil), andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

The compositions of the present invention may also containpreservatives, wetting agents, emulsifying agents, and dispersingagents. Prevention of the action of microorganisms may be ensured by theinclusion of various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol sorbic acid, and the like. It may alsobe desirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the therapeutic agent,it is desirable to slow the absorption from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsuled matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, pills, powders, and granules. In such soliddosage forms, the active compounds are preferably mixed with at leastone pharmaceutically acceptable excipient or carrier such as sodiumcitrate or dicalcium phosphate and/or a) fillers or extenders such asstarches, lactose, sucrose, glucose, mannitol, and silicic acid, b)binders such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants suchas glycerol, d) disintegrating agents such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate, e) solution retarding agents such as paraffin, f)absorption accelerators such as quaternary ammonium compounds, g)wetting agents such as, for example, cetyl alcohol and glycerolmonostearate, h) absorbents such as kaolin and bentonite clay, and i)lubricants such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Inthe case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents as appropriate.

Solid compositions of a similar type may also be employed as fillers insoft and hard filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Illustrative examples of embedding compositionswhich can be used include polymeric substances and waxes.

The active αvβ3 integrin inhibitors can also be in micro-encapsulatedform, if appropriate, with one or more of the above-mentionedexcipients.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, solutions, suspensions,syrups and elixirs. In addition to the active compounds, the liquiddosage forms may contain inert diluents so commonly used in the art suchas, for example, water or other solvents, solubilizing, agents andemulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, dimethyl formamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions may also contain adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

In some embodiments of the invention the αvβ3 integrin inhibitor isadministered in the form of liposomes. As is known to those skilled inthe art, liposomes are generally derived from phospholipids or otherlipid substances. Liposomes are formed by mono- or multi-lamellarhydrated liquid crystals that are dispersed in an aqueous medium. Anynon-toxic, physiologically acceptable and metabolizable lipid capable offorming liposomes can be used. The present compositions in liposome formcan contain, in addition to the αvβ3 integrin inhibitor, stabilizers,preservatives, excipients, and the like. Preferred lipids arephospholipids and phosphatidyl cholines (lecithins), both natural andsynthetic. Methods to form liposomes am known in the art. See, e.g.,Prescott, ed., METHODS IN CELL BIOLOGY, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

One of ordinary skill will appreciate that effective amounts of thetherapeutic agents used in the methods of the invention can bedetermined empirically and may be employed in pure form or, where suchforms exist, in pharmaceutically acceptable salt, ester or prodrug form.The therapeutic agents may be administered in compositions incombination with one or more pharmaceutically acceptable excipients. Itwill be understood that, when administered to a human patient, the totaldaily usage of the agents and compositions of the present invention willbe decided by the attending physician within the scope of sound medicaljudgment. The specific therapeutically effective dose level for anyparticular patient will depend upon a variety of factors including thetype and degree of the response to be achieved; the specific agent orcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the agent or composition; the duration of thetreatment; drugs (such as a chemotherapeutic agent) used in combinationor coincidental with the specific composition; and like factors wellknown in the medical arts.

Techniques of dosage determination are well known in the art. Forexample, satisfactory results are obtained by oral administration oftherapeutic dosages on the order of from 0.05 to 10 mg/kg/day,preferably 0.1 to 7.5 mg/kg/day, more preferably 0.1 to 2 mg/kg/day,administered once or, in divided doses, 2 to 4 times per day. Onadministration parenterally, for example by i.v. drip or infusion,dosages on the order of from 0.01 to 5 mg/kg/day, preferably 0.05 to 1.0mg/kg/day and more preferably 0.1 to 1.0 mg/kg/day can be used. Suitabledaily dosages for patients are thus on the order of from 2.5 to 500 mgp.o., preferably 5 to 250 mg per oral (p.o.), more preferably 5 to 100mg p.o., or on the order of from 0.5 to 250 mg i.v., preferably 2.5 to125 mg i.v. and more preferably 2.5 to 50 mg i.v.

The administration of the agents of the present invention may be foreither prophylactic or therapeutic purpose. When providedprophylactically, the agent is provided in advance of any damage i.e.,proteinuria or podocyte damage. The prophylactic administration of theagent serves to prevent or reduce the rate of onset of symptoms. Whenprovided therapeutically, the agent is provided at (or after) the onsetof the appearance of symptoms of actual disease. The therapeuticadministration of the agent serves to reduce the severity and durationof proteinuria.

The compositions of the invention are administered in effective amounts.An “effective amount” is that amount of any of the compositions providedherein that alone, or together with further doses, produces the desiredresponse, e.g. reduces or eliminates proteinuria. This may involve onlyslowing the progression of the disease temporarily, although morepreferably, it involves halting the progression of the diseasepermanently. This can be monitored by routine methods. The desiredresponse to treatment of the disease or condition also can be delayingthe onset or even preventing the onset of the disease or condition. Anamount that is effective can be the amount of a αvβ3 integrin inhibitoralone which produces the desired therapeutic endpoint. An amount that iseffective is also the amount of a αvβ3 integrin inhibitor in combinationwith another agent that produces the desired result.

Such amounts will depend, of course, on the particular condition beingtreated, the severity of the condition, the individual patientparameters including age, physical condition, size and weight, theduration of the treatment, the nature of concurrent therapy (if any),the specific route of administration and like factors within theknowledge and expertise of the health practitioner. These factors arewell known to those of ordinary skill in the art and can be addressedwith no more than routine experimentation. It is generally preferredthat a maximum dose of the individual components or combinations thereofbe used, that is, the highest safe dose according to sound medicaljudgment. It will be understood by those of ordinary skill in the art,however, that a patient may insist upon a lower dose or tolerable dosefor medical reasons, psychological reasons or for virtually any otherreasons.

The doses of αvβ3 integrin inhibitors administered to a subject can bechosen in accordance with different parameters, in particular inaccordance with the mode of administration used and the state of thesubject. Other factors include the desired period of treatment. In theevent that a response in a subject is insufficient at the initial dosesapplied, higher doses (or effectively higher doses by a different, morelocalized delivery route) may be employed to the extent that patienttolerance permits.

Based upon the composition, the dose can be delivered continuously, suchas by continuous pump, or at periodic intervals. Desired time internalsof multiple doses of a particular composition can be determined withoutundue experimentation by one skilled in the art. Other protocols for theadministration of the compositions provided will be known to one ofordinary skill in the art, in which the dose amount, schedule ofadministration, site of administration, mode of administration and thelike vary from the foregoing.

Administration of αvβ3 integrin inhibitor compositions to mammals otherthan humans, e.g. for testing purposes or veterinary therapeuticpurposes, is carried out under substantially the same conditions asdescribed above.

The compositions of the present invention have in vitro and in vivodiagnostic and therapeutic utilities. For example, these molecules canbe administered to cells in culture, e.g. in vitro or ex vivo, or in asubject, e.g., in vivo, to treat, prevent or diagnose a variety ofdisorders. As used herein, the term “subject” is used interchangeablywith the term “patient” and is intended to include humans and non-humananimals including but not limited to a dog, cat, horse, cow pig, sheep,goat, or primate, e.g., monkey. Preferred patients include a humanpatient having a proteinuric disorder, including disorders characterizedby proteinuria as described herein.

As used herein “a patient in need thereof” refers to any patient that isaffected with a disorder characterized by proteinuria. In one aspect ofthe invention “a patient in need thereof” refers to any patient that mayhave, or is at risk of having a disorder characterized by proteinuria.In one embodiment of the invention “a patient in need thereof” is apatient that has, may have or is at risk at having cancer, precancer,refractory cancer or metastatic cancer. In yet another embodiment of theinvention “a patient in need thereof” is a patient that has, may have,or is at risk of having a cognitive disorder, such as Alzheimer'sdisease or dementia.

The compositions provided of the present invention can be used inconjunction with other therapeutic treatment modalities. Such othertreatments include surgery, radiation, cryosurgery, thermotherapy,hormone treatment, chemotherapy, vaccines, and immunotherapies.

The invention also relates in some aspects to the identification andtesting of candidate agents and molecules that may be αbβ3 integrininhibitors. These molecules are referred to as putative αvβ3 integrininhibitors. The putative αvβ3 integrin inhibitors can be screened foractivity using the same type of assays as described herein (e.g., theassays described in the Examples section). Using such assays, additionalαvβ3 integrin inhibitors can be can be identified.

The invention further provides efficient methods of identityingpharmacological agents or lead compounds as αvβ3 integrin inhibitors.Generally, the screening methods involve assaying for compounds whichinhibit the level of αvβ3 integrin activity. As will be understood byone of ordinary skill in the art, the screening methods may measure thelevel of binding between the molecules directly, such as by using themethods employed in the Examples. In addition, screening methods may beutilized that measure a secondary effect of the αvβ3 integrininhibitors, for example the level of proteinuria in a cell or tissuesample.

A wide variety of assays for pharmacological agents can be used inaccordance with this aspect of the invention, including, labeled invitro protein-protein binding assays, electrophoretic mobility shiftassays, immunoassays, cell-based assays such as two or three-hybridscreens, expression assays, etc. The assay mixture comprises a candidatepharmacological agent. Typically, a plurality of assay mixtures are runin parallel with different agent concentrations to obtain a differentresponse to the various concentrations. Typically, one of theseconcentrations serves as a negative control, i.e., at zero concentrationof agent or at a concentration of agent below the limits of assaydetection.

Putative inhibitors useful in accordance with the invention encompassnumerous chemical classes, although typically they are organiccompounds. Preferably, the putative modulators are small organiccompounds, i.e., those having a molecular weight of more than 50 yetless than about 2500, preferably less than about 1000 and, morepreferably, less than about 500. Putative αvβ3 integrin inhibitorscomprise functional chemical groups necessary for structuralinteractions with proteins and/or nucleic acid molecules, and typicallyinclude at least an amine, carbonyl, hydroxyl or carboxyl group,preferably at least two of the functional chemical groups and morepreferably at least three of the functional chemical groups. Theputative modulators can comprise cyclic carbon or heterocyclic structureand/or aromatic or polyaromatic structures substituted with one or moreof the above-identified functional groups. Putative modulators also canbe biomolecules such as peptides, saccharides, fatty acids, sterols,isoprenoids, purines, pyrimidines, derivatives or structural analogs ofthe above, or combinations thereof and the like. Where the putativemodulator is a nucleic acid molecule, the agent typically is a DNA orRNA molecule, although modified nucleic acid molecules as defined hereinare also contemplated.

It is contemplated that cell-based assays as described herein can beperformed using cell samples smiler cultured cells. Biopsy cells andtissues as well as cell lines grown in culture are useful in the methodsof the invention.

Putative αvβ3 integrin inhibitors are obtained from a wide variety ofsources including libraries of synthetic or natural compounds. Forexample, numerous means are available for random and directed synthesisof a wide variety of organic compounds and biomolecules, includingexpression of randomized oligonucleotides, synthetic organiccombinatorial libraries, phage display libraries of random peptides, andthe like.

Alternatively, libraries of natural compounds in the form of bacterial,fungal, plant and animal extracts are available or readily produced.Additionally, natural and synthetically produced libraries and compoundscan be readily be modified through conventional chemical, physical, andbiochemical means. Further, known pharmacological agents may besubjected to directed or random chemical modifications such asacylation, alkylation, esterification, amidification, etc. to producestructural analogs of the agents.

A variety of other reagents also can be included in the mixture. Theseinclude reagents such as salts, buffers, neutral proteins (e.g.,albumin), detergents, etc. which may be used to facilitate optimalprotein-protein and/or protein-nucleic acid binding. Such a reagent mayalso reduce non-specific or background interactions of the reactioncomponents. Other reagents that improve the efficiency of the assay suchas antimicrobial agents, and the like may also be used.

The prerequisite for producing intact native polypeptides using E. coliis the use of a strong, regulatable promoter and an effective ribosomebinding site. Promoters which may be used for this purpose include thetemperature sensitive bacteriophage λ_(pL)-promoter, the tac-promoterinducible with IPTG or the T7-promoter. Numerous plasmids with suitablepromoter structures and efficient ribosome binding sites have beendescribed, such as for example pKC30 (λ_(pL); Shimatake and Rosenberg,Nature 292:128 (1981), pKK173-3 (tac, Amann and Brosius, Gene 40:183(1985)) or pET-3 (T7-promoter (Studier and Moffat, J. Mol. Biol. 189:113(1986)).

A number of other suitable vector systems for expressing the DNAaccording to the invention in E. coil are known from the prior art andare described, for example, in Sambrook et al., Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press (1989)).

Suitable E. coil strains which are specifically tailored to a particularexpression vector are known to those skilled in the art (Sambrook etal., Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press (1989)). The experimental performance of the cloningexperiments, the expression of the polypeptides in E. coli and theworking up and purification of the polypeptides are known and aredescribed, for example, in Sambrook et al., Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory Press (1989). Inaddition to prokaryotes, eukaryotic microorganisms such as yeast mayalso be used.

For expression in yeast, the plasmid YRp7 (Stinchcomb et al. Nature282:39 (1979); Kingsman et al., Gene 7:141 (1979); Tschumper et al.,Gene 10:157 (1980)) and the plasmid YEp13 (Bwach et al., Gene 8:121-133(1979)) are used, for example. The plasmid YRp7 contains the TRP1-genewhich provides a selection marker for a yeast mutant (e.g., ATCC No.44076) which is incapable of growing in tryptophan-free medium. Thepresence of the TRP1 defect as a characteristic of the yeast strain usedthen constitutes an effective aid to detecting transformation whencultivation is carried out without tryptophan. The same is true with theplasmid YEp13, which contains the yeast gene LEU-2, which can be used tocomplete a LEU-2-minus mutant.

Other suitable marker genes for yeast include, for example, the URA3-and HIS3-gene. Preferably, yeast hybrid vectors also contain areplication start and a marker gene for a bacterial host, particularlyE. coli, so that the construction and cloning of the hybrid vectors andtheir precursors can be carried out in a bacterial host. Otherexpression control sequences suitable for expression in yeast include,for example, those of PHO3- or PHO5-gene.

Other suitable promoter sequences for yeast vectors contain the5′-flanking region of the genes of ADH I (Ammerer, Methods of Enzymology101:192-210 (1983)), 3-phosphoglycerate kinase (Hitzeman et al., J Biol.Chem. 255:2073 (1980)) or other glycolytic enzymes (Kawaski andFraenkel, BBRC 108:1107-1112 (1982)) such as enolase,glycerinaldehyde-3-phosphate-dehydrogenase, hexokinase,pyruvate-decarboxylase, phosphofructokinase, glucose-6-phosphateisomerase, phosphoglucose-isomerase and glucokinase. When constructingsuitable expression plasmids, the termination sequences associated withthese genes may also be inserted in the expression vector at the 3′-endof the sequence to be expressed, in order to enable polyadenylation andtermination of the mRNA.

Generally, any vector which contains a yeast-compatible promoter andorigin replication and tennination sequences is suitable. Thus, hybridvectors which contain sequences homologous to the yeast 2 μ plasmid DNAmay also be used. Such hybrid vectors are incorporated by recombinationwithin the cells of existing 2 μ-plasmids or replicate autonomously.

In addition to yeasts, other eukaryotic systems may, of course, be usedto express the polypeptides according to the invention. Sincepost-translational modifications such as disulphide bridge formation,glycosylation, phosphorylation and/or oligomerization are frequentlynecessary for the expression of biologically active eukaryotic proteinsby means of recombinant DNA, it may be desirable to express the DNAaccording to the invention not only in mammalian cell lines but alsoinsect cell lines.

Functional prerequisites of the corresponding vector systems comprise,in particular, suitable promoter, termination and polyadenylationsignals as well as elements which make it possible to carry outreplication and selection in mammalian cell lines.

In a preferred embodiment of the invention particularly suitablepromoters are podocyte specific promoters. A podocyte specific promoteris one that is expressed exclusively in podocytes, such as the podocinpromoter.

For expression of the DNA molecules according to the invention it isparticularly desirable to use vectors which are replicable both inmammalian cells and also in prokaryotes such as E. coil. Vectors derivedfnom viral systems such as SV40, Epstein-Barr-virus etc., include, forexample, pTK2, pSV2-dhfv, pRSV-neo, pKO-neo, pHyg, p205, pHEBo, etc.(Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Press, N.Y. (1989)).

After transformation in suitable host cells, e.g. CHO cells,corresponding transformed cells may be obtained with the aid ofselectable markers (thymidine-kinase, dihydrofolate-reductase, greenfluorescent protein, etc.) and the corresponding polypeptides areisolated after expression. The host cells suitable for the vectors areknown, as are the techniques for transfomiation (nricro-injection,electroporation, calcium phosphate method, etc.) as described, forexample, in Sambrook et al., Molecular Cloning: A Laboratory Manual,Cold Spring Harbor Press, N.Y. (1989).

For cloning corresponding DNA fragments in prokaryotic or eukaryoticsystems, the selected vector may be cut, for example, with a restrictionendonuclease and, optionally after modification of the linearized vectorthus formed, an expression control sequence equipped with correspondingrestriction ends is inserted. At the 3′-end (in the direction oftranslation) the expression control sequence contains the recognitionsequence of a restriction endonuclease, so that the vector alreadycontaining the expression control sequence is digested with the saidrestriction enzyme and the DNA molecule according, to the invention,provided with ends which fit, can be inserted. It is advantageous tocleave the vector which already contains the expression control sequencewith a second restriction endonuclease inside the vector DNA and toinsert the DNA molecule provided with the correct ends into the vectorfragment produced. The techniques required are described, for example,by Sambrook et al. Molecular Cloning: A Laboratory Manual Cold SpringHarbor Press. N.Y. (1989).

Apart from the DNA molecules specified, the invention also relates toprocesses for preparing the vectors described herein, particularlyexpression vectors. These vectors are characterized in that a DNAprovided with corresponding ends and coding for a functional derivativeor a fragment of the protein is inserted into a vector DNA cut withrestriction endonucleases and containing the expression controlsequences described by way of example, in such a way that the expressioncontrol sequences regulate the expression of the DNA inserted. Thepeptides and antibody agents of the present invention which are obtainedby the expression of recombinant DNA or from the native receptormolecule may, of course, also be derivatized by chemical or enzymaticprocesses.

Also within the scope of the invention are kits comprising thecompositions of the invention and instructions for use. The kits canfurther contain at least one additional reagent, such as achemotherapeutic agent.

A kit may comprise a carrier being compartmentalized to receive in closeconfinement therein one or more container means or series of containermeans such as test tubes, vials, flasks, bottles, syringes, or the like.A first of said container means or series of container means may containone or more αbβ3 integrin inhibitors or recombinant vectors for theexpression thereof. A second container means or series of containermeans may contain a second therapeutic, such as, cytotoxic drug or αvβ3integrin antibodies (or fragment thereof).

Kits for use in the therapeutic methods of the invention containing theαvβ3 integrin inhibitors conjugated to other compounds or substances canbe prepared. The components of the kits can be packaged either inaqueous medium or in lyophilized form. When the αvβ3 integrin inhibitorsor fragments thereof are used in the kits in the form of conjugates inwhich a label or a therapeutic moiety is attached, such as a radioactivemetal ion or a therapeutic drug moiety, the components of suchconjugates can be supplied either in fully conjugated form, in the formof intermediates or as separate moieties to be conjugated by the user ofthe kit.

This invention is not limited in its application to the details ofconstruction and the arrangement of components set forth in thefollowing description or illustrated in the drawings. The invention iscapable of other embodiments and of being practiced or of being carriedout in various ways. Also, the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing,” “involving,” and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

The present invention is further illustrated by the following Examples,which in no way should be construed as further limiting. The entirecontents of all of the refinences (including literature references,issued patents, published patent applications, and co-pending patentapplications) cited throughout this application are hereby expresslyincorporated by reference.

EXAMPLES Example 1 Modification of Kidney Barrier function by theUrokinase Receptor

In this example, the role of uPAR was analyzed in the regulation ofstructure and function of podocytes during normal and diseaseconditions. Mice deficient for uPAR²⁰, uPA²¹, Vn²² and β3 integrin²³were challenged with lipopolysaccharide (LPS), a treatment known tocause FP effacement and proteinuria⁹. It is shown that uPAR isdispensable for normal renal filtration but required in podocytes butnot in endothelial cells for loss of renal permselectivity seen in humanand rodent kidney diseases. The proteinuric signal originating from uPARin podocytes is independent of urokinase and is required for podocyte FPeffacement and LPS-induced proteinuria.

Results

uPAR induction in human and rodent proteinuric diseases

We first tested if uPAR protein is expressed in human glomeruli (FIG.1A) and found expression in many glomerular cells including podocyteswhich are identified by synaptopoding labeling²⁵. Next, we investigatedthe expression of uPAR mRNA in human proteinuric renal diseases (FIG.1B). We performed quantitative real-time PCR using isolated glomerulifrom human kidney biopsies²⁶. We analyzed uPAR expression in RNA samplesfrom patients without glomerular disease (con, n=8) and in patients withfocal segmental glomerulosclerosis (FSGS, n=14) and diabetic nephropathy(DN, n=20), both conditions with podocyte FP effacement andproteinuria⁶. We found a low level of glomerular uPAR mRNA expression inpatients without glomerular disease (FIG. 1B). In contrast, patientswith biopsy-proven FSGS had a significant increase in glomerular uPARexpression (FSGS 0.35±0.17 vs con 0.14±0.02, **p<0.05), (FIG. 1B). Aneven stronger induction of glomerular uPAR mRNA expression (0.69±0.21 vscon 0.14±0.02, *p<0.012) was found in patients with diabetic nephropathy(FIG. 1B).

To test which cells in the glomerulus display increased uPAR expression,we examined the localization of uPAR within the kidney in threedifferent animal models of inducible proteinuria and podocyte FPeffacement, including the puromycin aminonucleoside nephrosis model inthe rat (PAN)²⁷, the mouse model of LPS-induced transient nephroticsyndrome⁹ and the NZB/W F1 murine model of systemic lupus erythematosus(SLE)²⁸. Using immunofluorescence and confocal microscopy, we found lowexpression of uPAR in glomeruli from control rats or mice (FIG. 1C).uPAR was partially localized in podocytes as indicated by doubleimmunofluorescent staining with synaptopodin²⁵. In contrast, expressionof uPAR protein in all three proteinuria models was significantlyincreased in glomerular cells including podocytes as demonstrated by theincreased yellow staining pattern resulting from overlap withsynaptopodin (FIG. 1C). Of note, in the NZB/W F1 Lupus mouse model, uPARwas preferentially found in nephritic areas of the glomerulus in a moresegmental distribution. Such a distribution has been recently reportedin marine glomerulonephritis where podocytes can populate cellularcrescents¹². In addition to glomerular uPAR labeling, we also foundexpression of uPAR in proximal tubular cells which appeared unchangedunder normal and disease conditions (data not shown). Increased uPARprotein expression was also observed in LPS and PAN treated culturedpodocytes (FIG. 7B) where uPAR was preferentially located at the cellmembrane (FIG. 7C). Analysis of the uPAR ligand Vn revealed a prominentstaining of Vn in podocytes of human kidney (FIG. 8A). We detected aninduction of Vn labeling in podocytes of PAN rats as well as of LPS andLupus mice when compared to controls (FIG. 8B). Overall, the expressionprofiles for Vn in podocytes were similar to the pattern we haveobserved for uPAR.

To define the subcellular localization of uPAR within the glomerularcells including podocytes, we have analyzed uPAR localization in normaland diabetic animals (FIG. 1D), since uPAR mRNA induction is strongestduring diabetic nephropathy in humans (FIG. 1B). We carried outsemiquantitative immunogold analysis of uPAR and transmission electronmicroscopy in glomerular walls of normal and 3 months as well as 12months old diabetic rats in which hyperglycemia was induced bystreptozotocin injection²⁹. Under normal conditions, uPAR expression wasfound in all cell types of the glomerulus (Table 1) including podocytes(FIG. 1D). Morphometrical analysis revealed a homogeneous distributionof uPAR in podocytes, mesangial and endothelial cells (Table 1). 12months old diabetic rats displayed increased uPAR labeling in all cellsof the glomerular wall (FIG. 1E). Endothelial uPAR expression wasstronger in luminal and basal membrane aspects when compared tocontrols. Interestingly, podocyte uPAR was increased in 3 and 12 monthsdiabetic rats but only in basal membrane aspects of the FPs. Mesangialcells expressed high levels of uPAR with no difference under normal anddiseased conditions.

uPAR in Podocytes is Required for Foot Process Effacement andProteinuria

To explore whether uPAR has a direct role in the regulation of podocyteFP structure and function, we next compared FP morphology of wild typeand uPAR^(-/-) mice³⁰ before and after the administration of LPS.Morphologically, there was no diffemace between the structure ofpodocyte FP in wild type or uPAR^(-/-) mice (FIG. 2A, con). However, 24h after LPS injection, we found podocyte FP effacement in wild type butnot in uPAR^(-/-) mice (FIG. 2A, LPS), suggesting a functional linkbetween the development of podocyte FP effacement and uPAR expression.To test whether the protection from LPS-induced FP effacement could beovercome by restoring glomerular uPAR in uPAR^(-/-) mice, we utilizedour previously reported gene delivery protocol to deliveruPAR-cDNA^(31, 32, 8). 24 h after gene delivery of a plasmid encodinguPAR but not of an empty vector control, we found uPAR expression inglomerular cells including podocytes of uPAR^(-/-) mice, as confirmed bydouble-immunofluorescent labeling of uPAR and synaptopodin (FIG. 2B). Tomonitor the expression levels of uPAR after gene delivery, we performedimmunoblots. 14 h after uPAR gene delivery, uPAR protein was found inthe liver, and at lower expression levels in glomerular extracts (FIG.2C). The restoration of uPAR did change the morphology of podocyte FPs(FIG. 2D, con).

However, concomitant administration of LPS and uPAR-cDNA into uPAR^(-/-)mice resulted in FP effacement (FIG. 2D, LPS), similar to LPS-treatedwild type animals (FIG. 2A, LPS). In contrast, we did not find any FPchanges in uPAR^(-/-) mice which had received vector control, even afterco-administration of LPS (FIG. 2D, LPS).

To study the functional consequences of uPAR reconstitution on thedevelopment of proteinuria, we analyzed the urine protein excretion ofwild type, uPAR^(-/-), and uPAR-reconstituted uPAR^(-/-) mice before andafter LPS injection (FIG. 2E). Whereas PBS treated control mice and uP4R⁴⁻ mice did not display any significant proteinuria, the injection ofLPS induced significant proteinuria in wild type but not in uPAR^(-/-)mice and uPAR^(-/-) mice which received control plasmids. These dataindicate that uPAR^(-/-) mice were protected from urinary protein loss.Most importantly, uPAR^(-/-) mice reconstituted with uPAR-cDNA developheavy proteinuria but like wild type mice only after LPS injection (FIG.2E). The degree of proteinuria was comparable in LPS treated wild typeand uPAR-cDNA reconstituted uPAR^(-/-) mice. In summary, these datastrongly suggest that uPAR is required for the development ofLPS-indueed proteinuria in mice.

Even so it appears most logical that uPAR exerts its effects onproteinuria development by orchestrating podocyte FP effacement, itseemed still possible that uPAR in glomerular endothelial cells iscontributing as well. Thus, we carried out gene-transfer of uPAR cDNAunder the control of two different cell-specific promoter allowingcell-specific expression in podocytes (Podocin-uPAR),³³ or endothelialcells (ICAM2-uPAR)³⁴ (FIG. 2F). Cell-type specific expression of uPARwas monitored by double-immunofluorescence labeling with synaptopodin orthe endothelial marker CD31³⁵ (FIG. 2G). While the expression of uPAR inpodocytes was required for LPS-induced proteinuria, the expression ofuPAR in endothelial cells was associated with LPS resistance. Theseresults demonstrate that podocyte-uPAR is required and sufficient forLPS induced proteinuria.

uPAR Orchestrates Podocyte Motility

To begin to understand uPAR function in podocytes, we were consideringuPAR's role in cell motility¹⁶. Podocyte PP effacement may represent amotile event resulting in spreading of podocyte FPs on the GBM. Thus, westudied podocyte motility in cultured podocytes before and after stableknockdown of uPAR using stable siRNA. The efficiency of uPAR-siRNA wasconfirmed by both semi-quantitative RT-PCR (FIG. 9A) and Westernblotting (FIG. 9B). We then used a modified multi-well Boyden chamberassay to assess the random migration of differentiated podocytes on typeI collagen (data not shown) and Vn, a known binding partner of uPAR¹⁰which is induced in proteinuric glomeruli (FIG. 8B). LPS- orPAN-treatment for 24 h significantly promoted migration of wild typepodecytes (FIG. 3A, B). In contrast, the knockdown of uPAR significantlydecreased the number of migrating podocytes under normal condition andafter treatment with LPS or PAN (FIG. 3A, B). These results demonstratethat podocytes migrate in larger number in response to LPS or PAN andthat uPAR is necessary for podocyte cell migration.

We then analyzed the role of uPAR in the spatial motility of podocytesusing a modified scrape wound assay¹¹. Migrated podocytes were countedat different time points and the distance migrated by cells from thewound margin was related to the total width of the scar. Compared tocontrol cells, LPS or PAN treatment significantly promoted podocytewound closure after 24 h (FIG. 3C, D), a finding which was also obtainedin a similar pattern at timepoints 12, 24 and 48 h (FIG. 9C). Theaddition of external urokinase did not alter podocyte directionalmigration (FIG. 9D) but the knockdown of uPAR strongly reduced podocytedirected motility before and after administration of LPS or PAN, leavingthe wound largely unpopulated (FIG. 3C, D), (FIG. 9C). Together, thesedata suggest that uPAR is important for random as well as directedpodocyte migration,

uPAR Activates αbβ3 Integrin in Podocytes

Since uPAR is a GPI-anchored protein without a cytoplasmic tail, it isgenerally believed that signal transduction from uPAR involves lateralinteractions with membrane proteins such as integrins¹⁶. Most recently,a paper by Madsen et al. described that uPAR induced cell adhesion andmigration required Vn binding which can occur independently of uPARinteractions with integrins¹⁹. Podocyte motility on Vn is enhanced in auPAR-dependent fashion (FIG. 3) and Vn is induced in glomeruli duringproteinuria (FIG. 8B). Thus, it appeared possible that an uPAR-Vncomplex or an uPAR-Vn-integrin complex facilitates podocyte motility andpromotes FP effacement in response to LPS. Integrins can be in aninactive or active conformation (FIG. 4A). The latter is stimulated bythe association with interacting agonists such as domain 3 of uPAR whichis important for a5b1 integrin interaction^(37, 38). Degryse andcolleagues recently identified an integrin-interacting sequence indomain 2 of uPAR, that acts as a new chemotactic epitope activatingαbβv3-dependent signaling pathways³⁹. Given our findings of uPAR and Vnin the glomerulus, we were particulary interested in the Vn receptorαbβ3 integrin³⁶. Indeed, the localization of αvβ3 integrin in podocyteFPs (FIG. 4B)³¹ and the distribution of uPAR (FIG. 4B) was similar. Inaddition, uPAR interacts with β3 integrin (FIG. 10A). Thus, wehypothesized that αvβ3 integrin may provide a functional link betweenuPAR, podocyte migration and proteinuria development. The geneticdeletion of β3 integrin or of the αvβ3 integrin ligand Vn resulted inprotection from proteinuria when challenged with LPS (FIG. 4C). Thismeans that both, Vn and β3 integrin are required for LPS-inducedproteinuria but either one is dispensable for normal renal developmentand function (FIG. 4C). Given the extent of published uPAR interactomeand the importance of α3 β1 integrin in podocyte development⁴⁰, we alsoanalyzed the potential contribution of α3β1 in integrin in the uPARsignaling cascade in podocytes and utilized a cDNA for uPAR whichencodes the uPAR mutant D262A that is unable to bind α3β1 integrin inhumans³⁸ and mouse (FIG. 10B). The expression of this type of uPAR inpodocytes led to the development of LPS-induced proteinuria supportingthe idea that uPAR in podocytes preferntially signals through αbβ3integrin. Since uPAR is involved in pathways dependent and independentof urokinase¹⁶, we also explored the contribution of urokinase onuPAR-dependent proteinuria pathways. We utilized UPA^(-/-) mice andtreated them with LPS. Interestingly, these mice developed proteinuriasuggesting that uPA is not required for the LPS-mediated effects of uPARon the kidney filtration barrier (FIG. 4C).

uPAR^(-/-), β3 integrin^(-/-) and Vn^(-/-) mice huge no overt renalphenotypes under normal conditions suggesting that uPAR signaling inpodocytes is not required for normal glomerular filtration. On the otherhand, all these molecules are required for the development of urinaryprotein loss. Based on this, we reasoned that changes in activation ofαvβ3 integrin under disease conditions may be a cause for the increasedpodocyte motility and FP effacement after the administration of LPS. Toexplore this idea, we next studied the expression of total and active β3integrin in kidney sections from wild type and uPAR^(-/-) mice. Totalpodocyte β3 integrin expression was visualized by double labeling of β3integrin with the podocyte marker synaptopodin wild type and uPAR^(-/-)mice before and after injection of LPS (FIG. 5A). The expression of β3integrin in podocytes was unchanged in wild type and uPAR^(-/-) micebefore and after LPS administration (FIG. 5A). We next studied thepresence of the active form of β3 integrin which can be detected by theuse of the well-defined antibody AP5. This antibody recognizes anN-terminal epitope of β3 integrin that is only accessible when theintegrin is in its active conformation⁴¹. To test if AP5 was capable todetect active β3 integrin in podocytes, we first evaluated the effect ofdivalent cations on the binding pattern of AP5 to β3 integrin by flowcytometry in normal (data not shown) and LPS treated cultured podocytes(FIG. 5B). We found a similar calcium-dependent binding pattern of AP5as previously reported for the binding of AP5 to β3 integrin in othercells⁴². Immunofluorescence of active β3 integrin with AP5 antibody inglomeruli suggest a low baseline activity of β3 integrin in wild typeand uPAR^(-/-) mice under normal conditions. This finding suggests thatαbβ3 integrin has a low basal activity even in the absence of uPAR. LPStreatment of wild type mice was associated with a strong induction ofpodocyte AP5 labeling (FIG. 5C, WT+LPS). This induction was absent inLPS treated uPAR^(-/-) mice (FIG. 5C, uPAR^(-/-)+LPS). We also observedcolocalization of AP5 labeling at sites of uPAR overexpression inpodocytes but not in podocytes in which uPAR was downregulated usingsiRNA (FIG. 5D). As an additional readout for active β3 integrin, weanalyzed the activity of the small GTPases cdc42 and Rac1 in glomerularlysates from wild type and uPAR^(-/-) mice before and afteradministration of LPS (FIG. 5E)⁴³. The activity of Rac1 was increased inLPS treated wild type but not uPAR^(-/-) mice (FIG. 5E, upper panel). Weobserved a similar induction pattern for cdc42 activity (FIG. 5E, lowerpanel). Of note, we could not detect activity for RhoA under normal anddisease conditions in wild type or uPAR^(-/-) mice (data not shown). Insome experiments we co-injected wild type mice with LPS andcyclo-[Arg-Gly-Asp-D-Phe-Val] RGDfV known from clinical cancer trials asCilengitide which is used as a specific inhibitor of αvβ3 integrin⁴⁴.This treatment inhibited the induction of active Rac1 and cdc42 inglomeruli of LPS treated mice (FIG. 5E). Together, these findingssupport the concept that uPAR is required for the activation of podocyteαvβ3 integrin after LPS treatment.

We next explored possible subcellular compartments where uPAR and β3integrin can associate with each other. Studies suggest that manyaspects of the podocyte FP membrane as well as the SD are rich incholesterol⁴⁵ and several SD proteins like podocin and nephrin areassociated with lipid rafts⁴⁶. Plasma membrane lipid rafts help tocompartmentalize signal transduction events within different regions²⁴and uPAR as a GPI-anchored protein is known to be found in lipid richmembrane compartments¹⁶. We wondered whether uPAR and β3 integrinassociate together within lipid rafts in podocytes. We thereforeperformed sucrose density gradient assays of whole cellular extracts ofcultured podocytes before and after LPS administration (FIG. 6A). Wefound that uPAR and β3 integrin are mainly associated with the non-raftfractions in control podocytes. However, 24 h after LPS administration,both uPAR and β3 integrin were more enriched within the lipid raftfraction (FIG. 6A). The functional association of uPAR and β3 integrinwithin lipid rafts was further confirmed by the observation thatdisruption of lipid rafts using Methyl-β-cyclodextrin (MBCD)⁴⁷ abrogatedthe activation of β3 integrin in response to LPS in cultured podocytesas revealed by reduced AP5 staining (FIG. 6B). These data suggest thatβ3 integrin can be activated by uPAR within lipid rich domains of thepodocyte plasma membrane.

Pharmacological Interference with αvβ3 Integrin Modifies Proteinutia inMice

If the activation of αvβ3 integrin is an important downstream signalthat mediates the uPAR-induced cellular events in podocytes leading toproteinuria, expression of a constitutively active β3 integain should besufficient to induce proteinuria even in the absence of uPAR. Therefore,we utilized a β3 integrin cDNA which encodes a protein lackingaminoacids 616 to 690 of the carboxy-terminal regions of the β3ectodomain. This mutation confers constitutive activity to the β3protein and is expressed at the cell surface⁴⁸. We performed genetransfer of this active β3 integrin construct into uPAR^(-/-) mice. 24 hafter gene delivery of active β3 integrin, we monitored activity of β3integrin in podocytes by immunofluorescent double labeling ofsynaptopodin and WOW-1 antibody. WOW-1 antibody is known to recognizeconstitutive active β3 protein⁴⁹. uPAR^(-/-) mice positive for WOW-1labeling in the podocyte (FIG. 6D) developed proteinuria (FIG. 6D),while littermates which received normal β3 integrin or vector controlhad low podocyte labeling with WOW-1 antibody and no proteinuricresponse (FIG. 6D).

We also performed blocking experiments with an antibody inhibiting β3integrin function. Wild type mice which were co-injected with LPS and amonoclonal anti-β3 integrin antibody failed to develop proteinuria inresponse to LPS (FIG. 6E). This blocking antibody was also able toreduce podocyte motility significantly during the course of LPStreatment in vitro (FIG. 6D) connecting increased podocyte motility invitro with the development of proteinuria in vivo.

Finally, we used different concentrations ofcyclo-[Arg-Gly-Asp-D-Phe-Val] RGDfV (Cilengitide) to specifically blockαvβ3 integrin. Cyclo-RGDfV was injected in LPS treated wild type mice(FIG. 6G). While the administration of cyclo-RGDfV in normal mice had noeffect, mice which received LPS and cyclo-RGDfV displayed an attenuatedcourse of proteinuria in a dose dependent manner when compared tocontrol mice that had received only LPS. These data show that activityof αvβ3 integrin is important for proteinuria development and opensnovel avenues for the modulation of proteinuria by αvβ3 integrininterference in podocytes.

Methods Antibodies:

The following antibodies were used in this study: anti-active β3integrin (AP5), (GTI); anti-WOW-1 fragment antigen binding (Fab)⁴⁹ (kindgift from Sanford Shattil, La Jolla, Calif.); anti-CD61 blockingantibody (BD Pharmagen); anti-CD31 (ER-MP12) and anti-Vn (H-270),anti-uPAR (FL-290) (Santa Cruz Biotechnology, Inc); anti-uPAR-1 (R&DSystems); anti-α-tubulin (Calbiochem); anti-β3 integrin (ChemiconInternational); anti-CD61 (Sigma); anti-caveolin (Sigma); anti-GAPDH(Sigma); anti-Flag (Sigma); anti-HA (Sigma); anti-transferrin receptorand anti caveolini (Sigma); anti-synaptopodin mouse monoclonal antibody(G1), anti-synaptopodin rabbit polyclonal (NT), (Peter Mundel, N.Y.).

Animals and treatments:

All animal studies were approved by the Subcommittee on Research AnimalCare of the Massachusetts General Hospital. uPAR^(-/-) mice anduPA^(-/-) mice on a mixed background of 75% C57BL/6 and 25% 129 Swisswere obtained from University of Leuven, Belgium; Vn^(-/-) mice(C57BL/6) were obtained from Dr. David Ginsburg, University of Michigan;β3 integrin^(-/-) mice (C57BL/6) were obtained from Dr. RaghuramKalluri, Boston. C57BL/6 and 129 Swiss mice were purchased from JacksonLaboratory (Bar Harbor). The LPS mouse model was utilized as previouslydescribed⁹. The induction of B7-1 was used as a control for theeffectiveness of LPS. Rat PAN nephrosis model was set up by a singleintraperitoneal injection of puromycin (15 mg/100 g of body weight,Sigma-Aldrich) into Spragne-Dawley rats as described before²⁷. NZB/W F1mice were purchased from the Jackson Laboratory and analyzed after 20weeks when proteinuria and Lupus glomerulonephritis were present. Asdiabetic nephropathy rat model, we used Sprague Dawley rats treated withStreptozotocin. Hyperglycaemic state was induced by an intraperitonealStreptozotocin injection (50-70 mg/kg body weight, in citrate buffer 10mmol/L, pH 4.5). The hyperglycaemic state developed within 48 h and wasmaintained during the lifetime of the animals. No insulin administrationwas required. Glycosuria was evaluated with test strips of the UriscanTM (YD Diagnostics, VWR, Montréal, QC, Canada) and glycaemia with theAccuSoft Monitoring System (Roche Diagnostics, Laval, QC, Canada). Atthe end of the study, glycaemia values were 43±0.53 and 8.5±0.7 mmol/Lfor 3 months-old and 12 months-old normoglycaemic animals, respectively,and 21.2±0.9 and 33.9±4.0 mmol/L for 3 months-old and 12 months-olddiabetic animals, respectively.

Patients: Microdissected glomeruli from 34 patients with proteinuricdiseases and 8 control subjects were analyzed. Patients were stratifiedaccording to their histological diagnosis into focal and segmentalglomerulosclerosis (FSGS; n=14), and diabetic nephropathy (DN, n=20).For control biopsies, renal tissue was derived from pretransplantationkidney biopsies during cold ischemia time from 7 living and 1 cadavericdonors (n=8).

Quantitative real-time PCR: TaqMan real-time RT-PCR was done aspreviously reported²⁶. In brief, commercially available predevelopedTaqMan assay reagents (Applied Biosystems) were used for uPAR mRNAanalysis. The mRNA expression of uPAR was related to that ofsynaptopodin, which was used as a podocyte reference gene. Using thisapproach, the confounding factor of alterations in the proportion ofpodocyte cell number per total glomerular cells was counterbalanced, andonly RNA from the podocyte compartment of the glomerulus was integratedin the analysis, as demonstrated recently²⁶.

Immunohistochemistry: Human glomerular biopsies were fixed in coldacetone and stained with anti-uPAR antibodies, anti-Vn antibody andmonoclonal anti-synaptopodin antibody following standard protocols⁸.Mouse or rat kidneys were harvested and snap-frozen. Fixation andsectioning were performed following standard protocols⁸. Fordouble-immunofluorescent staining, sections were blocked for 30 min atroom temperature, and incubated with antibodies directed against:synaptopodin (G1, NT), β3 integrin (AP5, WOW-1), uPAR, Vn, CD31. Afterwashing with PBS, sections were incubated with appropriate fluorophoreconjugated secondary antibodies (Molecular Probes) for 50 min.Thereafter, sections were washed with PBS, and H₂O and mounted foranalysis with a confocal microscope (Bio-Rad Laboratories). For WOW-1labeling, uPAR^(-/-) mice were injected with β3_(Δ616-690) or wild typeβ3 integrin constructs. 14 h after iniection, mice were sacrificed andkidney was snap-frozen. Cyro-sections were cut at 4 μm and fixed withcold acetone for 10 min before incubated with WOW-1 Fab for 1 h. Afterwashing with PBS, the sections were then incubated with the secondaryantibody, anti-mouse Fab conjugated with 488 (Invitrogen) for 50 min andanalyzed by confocal microscopy.

Cultured podocytes were immunolabeled as described previously⁸.

Transmission electron microscopy (TEM), Immunoelectron microscopy (IEM)and Morphometry: TEM and IEM were performed according to the standardprotocols⁸. For morphometry of uPAR labeling across the glomerular wall,we used renal tissues from 3 and 12 months-old hyperglycaemic animalswith the corresponding age-matched normoglycaemic animals (3-4 animalsper group). Small pieces of renal cortex were sampled from theanaesthetized animal (urethane, 1 g per kg body weight). The tissuesamples were immediately fixed by immersion inperiodate-lysine-paraformaldehyde solution, dehydrated in gradedmethanol and embedded in Lowicryl, following protocols describedpreviously⁵².

For immunogold labeling, the grids carrying the ultra thin tissuesections were incubated on a drop of a saturated solution of sodiummetaperiodate for 10 min, washed with distilled water, transferred on adrop of 0.15 M glycine for 10 min and washed with PBS. Grids were thenincubated on a drop of ovalbumin 1% for 5 min and transferred to thediluted anti-uPAR antibody (1:10) overnight at 4° C. The grids werewashed with PBS and incubated on a drop of protein A-gold complex for 30min at room temperature. The grids were then washed with PBS (3×5 min)and distilled water (1×5min), dried and contrasted with uranyl acetate.Specificity of the immunolabelings was evaluated by control experiments,omitting the specific antibody step, replacing it with PBS.

Micrographs of immunolabeled renal glomeruli were recorded (>20micrographs per animal and timepoint), printed and evaluated throughmorphometrical techniques⁵². We measured the length of the endothelialluminal and abluminal membranes, that of podocyte basal and apicalmembranes and that of the mesangial cells, the number of gold particlesassociated to each of those membrane domains was then counted tocalculate the density of labeling. Results are expressed as number ofgold particles per μm of membrane (mean values±SEM). The measurementswere performed by direct planimetry and particle counting using an imageprocessing system (Videoplan 2, Carl Zeiss Inc., Toronto, Canada).

GTPase activity assay:

Rho family small GTPase activity in glomerular lysates was measured byRho/Rac/Cdc42 activation assay kit (Cell Biolabs, INC.) following themanufacturer's protocol. Isolated glomeruli from wild type anduPAR^(-/-) mice, some of them treated with LPS (t=0) and with RGDfVevery 8 hours for 24 hours were obtained by standard sieve technique²⁵.2 mg of glomerular lysate were used to prepare for positive or negativecontrol by incubating with 10 μl of GTPγS or GDP respectively. For smallGTPase pull-down assay, the same amount (2 mg) of glomerulus lysatesfrom different treatments were incubated with 40 μl of Rhotekin RBD orPAK PBD agarose bead slurry for 1 h at 4° C. After washing 3 times with1× assay buffer, beads were harvested and resuspended in LDS samplebuffer. Samples were heated for 10 min at 70° C. before SDS-PAGE. Afterelectrophoresis and protein transfer, the membranes were blocked with 5%milk, and incubated with anti-Rho, anti-Rac, and anti-Cdc42 antibodiesfor 1 h, followed by second antibody incubation and detection with ECL(Pierce). For loading control, 100 μg of glomerular lysates fromdifferent treatments were applied and immunoblotted with the sameanti-Rho, anti-Cdc42 and anti-Rac antibodies as used above.

In vivo Gene delivery:

uPAR-cDNA, plasmids were introduced into uPAR^(-/-) mouse using theTransIT in vivo gene delivery system (Mirus) as describedpreviously^(32, 8). The following cDNAs and vector constructs were usedfor gene delivery: uPAR; mutated uPAR D262A³⁸ (kind gift from Y Wei andHA Chapman, University of California, San Francisco); β3 integrin andthe constitutively active form of β3 integrin, D616-690 (β3Δ₆₁₆₋₆₉₀)⁴⁸;Podocin promoter vector p2.5³³ (a kind gift from Dr. LB Holzman,University of Michigan) for Pod-uPAR; ICAM-2 promoter vector³⁴ forICAM-2-uPAR. Tissues were analyzed for expression as describedpreviously⁸.

siRNA: Mouse uPAR siRNA (sense: CTTCCTGAAGTGTTGCAACTA) was constructedand inserted into a pRNA-H1.2/Neo vector (Genescript). Stabletransfection was done with podocytes maintaining at 33° C. byLipofectamine 2000 (Invitrogen). Positive clones were selected by G418(Sigma-Aldrich) at 500 μg/ml. For further experiments with uPAR siRNA,cells were grown under non-permissive conditions for 10-14 days beforeproceeded with migration experiments.

Flow cytometry:

To determine the activity of AP5 in mouse podocytes, cells were culturedunder non-permissive conditions for 10 days. Then medium was discardedand the cells were washed gently with PBS without Ca²⁺ and Mg²⁺. Thecells were then exposed to LPS right before they were incubated withvarious amounts of calcium in the presence of 5 μg/ml AP5 for 1 h: 1 mMEDTA, PBS without Ca²⁺ or Mg²⁺; 0.1 nM Cacl₂; 0.4 mM CaCl₂; 1 mM CaCl₂;2 mM CaCl₂. The cells were then harvested by cell scraper, washed andsubjected to flow cytometry analysis.

Cell culture and transient transfection:

HEK 293 cells were seeded on a 100 mm culture dish and maintained at 37°C. in DMEM with 10% FBS. Upon 90% confluent, cells were transtected withconstructs encoding uPAR or β3 integrin by Lipofectamine 2000(Invitrogen). 24 h after transfection, cells were harvested for furtherexperiments. Wild type podocytes were differentiated by culturing at 37°C. for at least 10 days (10 days for transfection and migration assay,14 days for other experiments).

Western blot and Co-immunoprecipitation:

For Western blotting, podocytes or extracted glomeruli were lysed inRIPA buffer containing a cocktail of protease inhibitors. The lysate wascentrifuged for 20 min at 12,000 rpm and the yielded supernatant wasfurther used. Bradford assay was performed to ensure equal amount ofloading. Proteins were separated and then transferred to a PVDFmembrane. After blocking for 30 min with 5% milk, the membrane wasincubated with primary antibody for 1 h, followed by secondary antibodyfor overnight 4° C. After washing, the membrane was visualized bychemiluminescence immunoblot detection kit (Pierce).

For Co-IP, HEK cells were co-transfected with constructs encoding uPAR,and β3 integrin for 24 h. Then cells were lysed in RIPA buffer with acocktail of protease inhibitors. The lysate was incubated with 25 μl ofFlag or HA agarose beads (Sigma) at 4° C., overnight after apre-cleaning. The beads were then washed 5 times with RIPA buffer andwere eluted by heating at 70° C. for 10 min. After a briefcentrifugation, the supernatants were ready for Western blotting.

Migration assay:

Podocyte migration was analyzed using a 12-well chemotaxis chamber(Neuro Probe) according to the manufacturer's protocol. In briefdifferentiated podocytes were treated with 50 μg/ml of LPS or PAN for 24h and then harvested for the migration assay. Bottom plates were coatedwith vitronectin or type I collagen, while upper plates were loaded withequal number of cells (5×10⁴) suspended in medium. The chamber wasincubated at 37° C. for 4 h before the membrane was taken out andstained with diamidino phenylindole (DAPI). The average number ofmigrated cells was counted in four fields in six independentexperiments.

To study the directional movement of podocytes, a wound healing assaywas performed. Briefly, podocytes were seeded on Vn or type I collagencoated cover-slips and cultured for 10 days at 37° C. before treatedwith LPS or PAN for 12-48 h. To create a scrape wound approximately 0.1cm wide, the narrow end of a P1000 pipette tip was perpendicularlypushed through the monolayer. Then, coverslips were washed twice withPBS and incubated in medium. After incubation, cells were fixed with 2%PFA and stained with DAPI for analysis. The cell migratory distance wascalculated by averaging the distance from the wound edge to themaximally migrated cell in five distinct border zones.

Sucrose gradient ultracentrifugation:

Podocyte lysate was overlaid with a sucrose step gradient andcentrifuged for 20 h at 120,000 g at 4° C. in a swing-out rotor. 10fractions (1 ml each) were collected starting from the top and analyzedby Western blotting with rafts, non-rafts markers, as well as uPAR andβ3 antibodies.

Blockade of β3 integrin in animals:

Cyclo-RGDfV (Biomol) was injected in mice at 1, 5 and 20 mg per kg bodyweight i.v. in mice every 8 h for three times. Control mice received thesame amount of PBS instead or the control peptide cyclo-RAD (Biomol),(data not shown). Immediately after the first injection, 200 □g of LPSwas injected intraperitoneally into each mouse to induce proteinuria. 24h after LPS injection, urine was collected for Braford assay.

For blockade of β3 integrin with the antibody CD61, wild type mice wererandomly divided into three groups (n=3 for each group) and injectedwith PBS alone (control), LPS+anti-CD61 or LPS+IgG isotype. The antibodywas administered 4 h after LPS injection through tail vein, with a finalconcentration of 10 □g/ml. Urine was collected at time points 0, 4 and24 h and analyzed by Bradford assay. Data represented in the figure wasbased on sample obtained after 24 h.

Statistical analysis:

Statistical analyses were performed by using a Student paired ornon-paired t-test when appropriate, and the null hypothesis was rejectedat the 0.05 level. Values were presented as Mean±SD, unless statedotherwise. Statistical comparisons for the morphometrical experimentswere performed using the Student t test and the Mann-Whitney U tests.

Example 2: Effect of Cyclo-RGDfV on Recovery of Proteinuria

The following example showed that CycloRGDfV also reduces alreadyexisting proteinuria (FIG. 11). B6 mice were injected LPS twice (0, 24h) with LPS to induce and maintain proteinuria. 48 h after firstinjection cycle-RGD (n=6) was administered (25 mg/kg body weight)through tail vein. Control (n=5) received the same amout of PBS. 0, 48h, 66 h urine was collected for Braford assay. The diagram shows thefold change of urinary protein at timepoint 66 h, *p<0.014.

Example 3: Effect of S247 on Recovery of Proteinuria

The following example shows that S247 also reduces already existingproteinuria. B6 mice are injected twice (0, 24 h) with LPS to induce andmaintain proteinuria. 48 h after first inection, S247 (n=6) isadministered (25 mg/kg body weight) through tail vein. Control (n=5)received the same amout of PBS. 0, 48 h, 66 h urine was collected forBraford assay. Reduction of urinary protein at timepoint 66 h by S247 isobserved.

Tablet 1

Quantitative analysis of uPAR expression and localization in normal anddiabetic glomeruli. uPAR is induced in podocyte foot processes of 3 and12 months old diabetic rats.

TABLE 1 uPAR morphometrical analysis Endothelial Luminal EndothelialPodocyte Podocyte Mesangial Membrane Basal Membrane Luminal MembraneBasal Membrane Membrane NORMAL 3 months 0.26 ± 0.06* 0.20 ± 0.05 0.24 ±0.03 0.19 ± 0.03 0.38 ± 0.05  (216.01 μm)** (213.89 μm) (576.86 μm)(258.95 μm) (196.62 μm) NORMAL 12 months 0.23 ± 0.06  0.18 ± 0.04 0.27 ±0.05 0.19 ± 0.05 0.30 ± 0.06 (144.63 μm) (141.51 μm) (288.68 μm) (138.03μm) (240.94 μm) DIABETIC 3 months 0.38 ± 0.05§ 0.27 ± 0.06 0.33 ± 0.03 0.29 ± 0.04§ 0.42 ± 0.06 (212.17 μm) (210.15 μm) (519.05 μm) (267.88μm) (213.83 μm) DIABETIC 12 months 0.36 ± 0.09§  0.37 ± 0.08§ 0.24 ±0.06  0.27 ± 0.03§ 0.41 ± 0.08 (219.79 μm) (234.75 μm) (586.03 μm)(256.68 μm) (253.73 μm) CONTROL of 0.02 ± 0.01  0.05 ± 0.03 0.05 ± 0.040.04 ± 0.03 0.07 ± 0.03 SPECIFICITY  (95.06 μm)  (89.29 μm) (133.65 μm) (75.57 μm) (172.70 μm) *particles per μm of membrane **total length ofmembrane measured §Significantly different from corresponding value ofnormal animals *p < 0.005, n = 3 animals for each time point

REFERENCES

1. Zandi-Nejad, K., Eddy, A. A., Glassock, R. J. & Brenner, B. M. Why isproteinuria an ominous biomarker of progressive kidney disease? KidneyInt Suppl, S76-89 (2004).

2. Kerjaschki, D. et al. A. beta 1-integrin receptor for fibronectin inhuman kidney glomeruli. Am J Pathol 134, 481-9 (1989).

3. Kreidberg, J. A. Functions of alpha3beta1 integrin. Curr Opin CellBiol 12, 548-53. (2000).

4. Regele, H. M. et al. Glomerular expression of dystroglycans isreduced in minimal change nephrosis but not in focal segmentalglomerulosclerosis. J Am Soc Nephrol 11, 403-12 (2000).

5. Reiser, J., Kriz, W., Kretzler, M. & Mundel, P. The glomerular slitdiaphragm is a modified adherens junction. J Am Soc Nephrol 11, 1-8(2000).

6. Durvasula, R. V. & Shankland, S. J. Podocyte injury and targetingtherapy: an update. Curr Opin Nephrol Hypertens 15, 1-7 (2006).

7. Tryggvason, K., Patrakka, J. & Wartiovnara, J. Hereditary proteinuriasyndromes and mechanisms of proteinuria. N Engl J Med 354, 1387-401(2006).

8. Sever, S. et al. Proteolytic processing of dynamin by cytoplasmiccathepsin L is a mechanism for proteinuric kidney disease. J Clin Invest117, 2095-2104 (2007).

9. Reiser, J. et al. Induction of B7-1 in podocytes is associated withnephrotic syndrome J Clin Invest 113, 1390-7 (2004).

10. Reiser, J. et al. Podocyte Migration during Nephrotic SyndromeRequires a Coordinated Interplay between Cathepsin L and {alpha}3Integrin. J Biol Chem 279, 34827-34832 (2004).

11. Asanuma, K. et al. Synaptopodin orchestrates satin organization andcell motility via regulation of RhoA signalling. Nat Cell Biol (2006).

12. Moeller, M. J. et al. Podocytes populate cellular crescents in amurine model of inflammatory glomerulonephritis. J Am Soc Nephrol 15,61-7 (2004).

13. Seiler, M. W., Venkatachalam, M. A. & Cotran, R. S. Glomerularepithelium: structural alterations induced by polycations. Science 189,390-3 (1975).

14. Gadea, G., de Toledo, M., Anguille, C. & Roux, P. Loss of p53promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices.J Cell Biol 178, 23-30 (2007).

15, Wei, Y. et al. Regulation of integrin function by the urokinasereceptor. Science 273, 1551-5 (1996).

16. Blasi, F. & Carmeliet, P. uPAR: a versatile signalling orchestrator.Nat Rev Mol Cell Biol 3, 932-43 (2002).

17. Alfano, M., Sidenius, N., Panzeri, B., Blasi, F. & Poli, G.Urokinase-urokinase receptor interaction mediates an inhibitory signalfor HIV-1 replication. Proc Natl Acad Sci U S A 99., 8862-7(2002).

18. Wei, Y. et al. Identification of the urokinase receptor as anadhesion receptor for vitronectin. J Biol Chem 269, 32380-8 (1994).

19. Madsen, C. D., Ferraris, G. M. , Andolfo, A., Cunningham, O. &Sidenius, N. uPAR-induced cell adhesion and migration: vitronectinprovides the key. J Cell Biol 177, 927-39 (2007).

20. Dewerchin, M. et al. Generation and characterization of urokinasereceptor-deficient mice. J Clin Invest 97, 870-8 (1996).

21. Carmeliet P. et al. Biological effects of disruption of thetissue-type plasminogen activator, urokinase-type plasminogen activator,and plasminogen activator inhibitor-1 genes in mice, Ann N Y Acad Sci748, 367-81; discussion 381-2 (1995).

22. Zheng X., Saunders, T. L., Camper, S. A., Samuelson, L. C. &Ginsburg, D. Vitronectin is not essential for normal mammaliandevelopment and fertility. Proc Natl Acad Sci USA 92, 12426-30 (1995).

23. Sund, M. et al. Function of endogenous inhibitors of angiogenesis asendothelium-specific tumor suppressors. Proc Natl Acad Sci U S A 102,2934-9 (2005).

24. Simons, K. & Toomre, D. Lipid Rafts and Signal Transduction, Nat RevMol Cell Biol 1, 31-39. (2000).

25. Mundel, P. et al. Synaptopodin: an actin-associated protein intelencephalic dendrites and renal podocytes. J Cell Biol 139, 193-204(1997).

26. Schmid, H. et al. Validation of endogenous controls for geneexpression analysis in microdissected human renal biopsies. Kidney Int64, 356-60 (2003).

27. Nakamura, T., Ebihara, I., Shirato, I., Tomino, Y. & Koide H.Modulation of basement membrane component gene expression in glomeruliof aminonucleoside nephrosis. Lab Invest 64, 640-7 (1991).

28. Kelley V. E. & Cavallo, T. An ultrastructural study of theglomerular slit diaphragm in New Zealand black/white mice. Lab Invest35,213-20 (1976).

29. Mauer, S. M. et al. Effects of kidney and pancreas transplantationon streptozotocin-induced malignant kidney tumors in rats. Cancer Res34, 1643-5 (1974).

30. Rijneveld, A. W. et al. Urokinase receptor is necessary for adequatehost defense against pnemuccoccal pneumonia. J Immunol 168, 3507-11(2002).

31. Mayer, G., Boileau, G. & Bendayan, M. Furin interacts withproMT1-MMP and integrin alphaV at specialized domains of renal cellplasma membrane. J Cell Sci 116, 1763-73 (2003).

32. Moller, C. C. et al. Induction of TRPC6 Channel in Acquired Forms ofProteinuric Kidney Disease. J Am Soc Nephrol (2006).

33. Moeller, M. J., Sanden, S. K., Soofi, A., Wiggins, R. C. & Holzman,L. B. Podocyte-specific expression of cre recombinase in transgenicmice. Genesis 35, 39-42 (2003).

34. Velasco, B. et al. Vascular gene transfer driven by endoglin andICAM-2 endothelial-specific promoters. Gene Ther 8, 897-904 (2001).

35. Zeisberg, E. M. et al. Endothelial-to-mesenchymal transitioncontributes to cardiac fibrosis. Nat Med 13, 952-61 (2007).

36. Arnaout, M. A., Mahalingam, B. & Xiong, J. P. Integrin structure,allostery, and bidirectional signaling. Annu Rev Cell Dev Biol 21,381-410 (2005).

37. Chaurasia, P. et al. A region in urokinase plasminogen receptordomain III controlling a functional association with alpha5beta1integrin and tumor growth. J Biol Chem 281, 14852-63 (2006).

38. Wei, Y. et al. Urokinase receptors are required for alpha 5 beta 1integrin-mediated signaling in tumor cells. J Biol Chem 282, 3929-39(2007).

39. Degryse, B., Resnati, M., Czekay, Loskutoff D. J. & Blasi, F. Domain2 of the urokinase receptor contains an integrin-interacting epitopewith intrinsic signaling activity: generation of a new avβ3 integrininhibitors. J Biol Chem 280, 24792-803 (2005).

40. Kreidberg, J. A. et al. Alpha 3 beta 1 integrin has a crucial rolein kidney and lung organogenesis. Development 122, 3537-47 (1996).

41. Pelletier, A. J., Kunicki, T. & Quaranta, V. Activation of theintegrin alpha v beta 3 involves a discrete cation-binding site thatregulates confirmation. J Biol Chem 271, 1364-70(1996).

42. Honda, S. et al. Topography of ligand-induced binding sites,including a novel cation-sensitive epitope (AP5) at the amino terminus,of the human integrin beta 3 subunit. J Biol Chem 270, 11947-54 (1995).

43. Dormond, O., Foletti, A., Paroz, C. & Ruegg, C. NSAIDs inhibit alphaV to 3 integrin-mediated and Cdc42/Rac-dependent endothelial-cellspreading, migration and angiogenesis. Nat Med 7, 1041-7 (2001).

44. Cai, W. & Chen, X. Anti-angiogenic cancer therapy based on integrinalphavbeta3 antagonism. Anticancer Agents Med Chem 6, 407-28 (2006).

45. Orci, L., Singh, A. Amherdt, M., Brown, D. & Perrelet, A.Microheterogeneity of protein and sterol content in kidney podocytemembrane. Nature 293, 646-7 (1981).

46. Schwarz, K. et al. Podocin, a raft-associated component of theglomerular slit diaphragm, interacts with CD2AP and nephrin. J ClinInvest 108, 1621-9 (2001).

47. Keller, P. & Simons, K. Cholesterol is required for surfacetransport of influenza virus hemagglutinin. J Cell Biol 140, 1357-67(1998).

48. Butta, N. et al. Disruption of the beta3 663-687 disulfide bridgeconfers constitutive activity to beta3 integrins. Blood 102, 2491-7(2003).

49. Pampori, N. et al. Mechanisms and consequences of affinitymodulation of integrin alpha(V)beta(3) detected with a novelpatch-engineered monovalent ligand. J Biol Chem 274, 21609-16 (1999).

50. de Jong, P. E. & Brenner, B. M. From secondary to primary preventionof progressive renal disease: the case for screening for albuminuria.Kidney Int 66, 2109-18 (2004).

51. Silberman, S., Janulis, M. & Schultz, R. M. Characterization ofdownstream Ras signals that induce alternative protease-dependentinvasive phenotypes. J Biol Chem 272, 5927-35 (1997).

52. Gugliucci, A. & Bendayan, M. Reaction of advanced glycationendproducts with renal tissue from normal and streprozotocin-induceddiabetic rats: an ultrastructural study using colloidal goldcytochemistry. J Histochem Cytochem 43, 591-600 (1995).

It has now been found that compounds of formula (I)

-   -   cyclo {NX₁—R₁—CO—NX₂—R₂—CO—NX₃—R₃—CO—NX₄—R₄—CO—NX₅—R₅—CO]        where:    -   R₁ is selected from:    -   CH(CH₂)₃NHC(NH)NH₂; C[CH_(n)F_(m)](CH₂)₃NHC(NH)NH₂    -   R₂ is the group CH₂; CH₂-CH₂;

-   -   R₃ is selected from CHCH₂COOH; C[CH_(n)F_(m)]CH₂-COOH;    -   R₄ is selected from CH-CH₂-Ph; C[CH_(n)F_(m)]CH₂-Ph;        CH-CH₂-(4-OH)Ph;    -   CH-CH₂-(4-OMe)Ph; CH-CH₂-(4-F)Ph; CH-CH(OH)-Ph; C(CH₃)₂;        CH-C(CH₃)₃; CH-CH₂-COOH;

-   -   R₅ is selected from CH-CH₂-Ph; C[CH_(n)F_(m)]CH₂-Ph;        CH-CH(CH₃)₂; C[CH_(n)F_(m)]CH(CH₃)₂; CH-C(CH₃)₃;    -   or, the NX₄-R₄-Co-NX5-R₅CO group is 3-aminomethyl-benzoyl n+m=3    -   X₁-X₅, which may be the same or diffetent, are H, (CH₂)_(n)-CH₃;        (CH₂)_(n)-

-   -   CHF₂; (CH₂)_(n)-CH₂F; (CH₂)_(n)-CFs where n=0-3;    -   with the proviso that at least one α-fluoroalkylated amino acid        is present in the formula (I) compound.    -   where each NX-R-CO amino acid can have an absolute type R or        type S configuration; their individual enantiomers,        diastereoisomers, the related mixtures, the pharmaceutically        acceptable salts are selective inhibitors of the a_(v)β₃ and/or        a_(v)β₅ integrin receptors.

Therefore, objects of the present invention are compounds of formula(I), as described above, a process for their preparation, their use asmedicaments and pharmaceutical compositions containing them.

Accordingly, we have found that this object is achieved by compounds ofthe formula I

-   -   B-G-L I    -   where B, G and L have the following meanings:    -   L is a structural element of the formula I_(L)    -   —U-T I_(L)    -   where    -   T is a group COOH, a radical hydrolyzable to COOH or a radical        bioisosteric to COOH and    -   —U— is —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, —CR_(L) ¹═CR_(L) ²—,        ethynylene or ═CR_(L) ¹—,        where    -   a is 0 or 1,    -   b is 0, 1 or 2,    -   X_(L) is CR_(L) ³R_(L) ⁴, NR_(L) ⁵, oxygen or sulfur,    -   R_(L) ¹, R_(L) ², R_(L) ³, R_(L) ⁴    -   independently of one another are hydrogen, —T, —OH, —NR_(L)        ⁶R_(L) ⁷, —CO—NH₂, a halogen radical, a branched or unbranched,        optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₃-C₇-cycloal-kyl, —CO—NH(C₁-C₆-alkyl),        —CO—N(C₁-C₆-alkly)₂ or C₁-C₄-alkoxy radical, an optionally        substituted radical C₁-C₂-alkylene-T, C₂-alkenylene-T or        C₂-alkynylene-T, an optionally substituted aryl or arylalkyl        radical or in each case independently of one another are two        radicals R_(L) ¹ R_(L) ² or R_(L) ³ and R_(L) ⁴ or optionally        R_(L) ¹ and R_(L) ³ together are an optionally substituted 3- to        7-membered saturated or unsaturated carbocycle or heterocycle,        which can contain up to three identical or different heteroatoms        O, N, S,    -   R_(L) ⁵, R_(L) ⁶, R_(L) ⁷    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-₆-alkyl, C₃-C₇-cycloalkyl,        CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl or CO—C₁-C₆-alkyl radical or        an optionally substituted CO—O-alkylenearyl, SO₂-aryl, CO-aryl,        SO₂-alkylenearyl or CO-alkylertearyl radical,    -   G is a structural element of the formula I_(G)

where

-   -   the structural element B is bonded via the ring nitrogen and the        structural element L is bonded to the structural element G via        W_(G),    -   Y_(G) is CO, CS, C═NR_(G) ² CR_(G) ³R_(G)-su-p.4,    -   R_(G) ² is hydrogen, a hydroxyl group, a branched or unbranehed,        optionally substituted C₁-C₆-alkyl, C₁-C₄-alkoxy,        C₃-C₇-cycloalkyl or —O—C₃-C₇-cycloalkyl radical or an optionally        substituted aryl, —O-aryl, arylalkyl or —O-alkylenearyl radical,    -   R_(G) ³, R_(G) ⁴    -   independently of one another are hydrogen or a branched or        unbranched, optionally substituted C₁-C₆-alkyl, C₂-C₆-alkyenyl,        C₂-C₆-alkynyl or C₁-C₄-alkoxy radical or both radicals R_(G) ³        and R_(G) ⁴ together are a cyclic acetal —O—CH₂—CH₂—O— or        —O—CH₂—O— or both radicals R_(G) ³ and R_(G) ⁴ together are an        optionally substituted C₃-C₇-cycloalkyl radical,    -   R_(G) ⁵ and R_(G) ⁶    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl or C₁-C₄-alkoxy        radical, an optionally substituted aryl or arylalkyl radical or        both radicals R_(G) ⁵ and R_(G) ⁶ together are an optionally        substituted, fused, unsaturated or aromatic 3- to 10-membered        carbocycle or heterocycle, which can contain up to three        different or identical heteroatoms O, N, S,    -   where in this fused, unsaturated or aromatic 3- to 10-membered        carbocycle or heterocycle, as substituents independently of one        another up to four substituents from the group consisting of    -   hydroxyl, halogen or a branched or unbranched, optionally        halogen-substituted C₁-C₄-aloxy, C₁-C₄-thioalkyl or C₁-C₄-alkyl        radical or an optionally halogen-substituted aryl, hetaryl or        C3-C₇-cycloalkyl radical or an optionally halogen-substituted        radical —SO₂—C₁-C₄-alkyl, SO₂—C₁-C₄-alkyl, —SO—C₁-C₄-alkyl,        —SO₂—C₁-C₄- alkylenearyl, —SO—C₁-C₄-alkylenearyl, —SO₂-aryl or        —SO-aryl are selected,    -   W_(G) is a structural element selected front the group of        structural elements of the formulae I_(W)G¹ to I_(W)G⁴, 2

-   -   RG₁ is hydrogen, halogen, a hydroxyl group or a branched or        unbranched, optionally substituted C₁-C₆-alkyl or C₁-C₄-alkoxy        radical,    -   R_(G) ⁷, R_(G) ⁸, R_(G) ⁹ R_(G) ¹⁰    -   independently of one another are hydrogen, a hydrogxl group,        —CN, halogen, a branched or unbranched, optionally substituted        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,        C₁-C₄-alkylene-C₃-C₇-cycloalkyl,        C₁-C₄-alkylene-C₃-C₇-heterocycloalkyl or        C₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl radical, a branched or        unbranched, optionally substituted radical C₁-C₄-alkylene-OR_(G)        ¹¹, C₁-C₄-alkylene-CO—OR-_(G) ¹¹, C₁-C₄-alkylene-O—CO—R_(G) ¹¹,        C₁-C₄-alkylene-CO-R_(G) ¹¹, C₁-C₄-alkylene-SO₂—NR_(G) ¹²R_(G)        ¹³, C₁-C₄-alkylene-CO—NR_(G)-¹²R_(G) ¹³,        C₁-C₄-alkylene-O—CO—NR_(G) ¹²R.su-b.G¹³, C₁-C₄-alkylene-NR_(G)        ¹²R_(G) ¹³ or C₁-C₄-alkylene-SR_(G) ¹¹,        C₁-C₄-alkylene-SO—R.-sub.G¹¹, a radical —S-R_(G) ¹¹, —O-R_(G)        ¹¹, —SO-R_(G) ¹¹, —SO₂—R_(G) ¹¹, —CO—OR_(G) ¹¹, —O—CO-R_(G) ¹¹,        —O—CO—NR_(G) ¹²R_(G) ¹³, —SO₂—NR_(G) ¹²G¹³, —CO—NR_(G) ¹²R_(G)        ¹³, —NR_(G) ¹²R_(G) ¹³ or CO-R_(G) ¹¹, an optionally substituted        C₃-C7-cycloalkyl, aryl, hetaryl, arylalkyl or hetarylalkyl        radical or in each case independently of one another two        radicals R_(G) ⁷ and R_(G) ⁹ or R_(G) ⁹ and R_(G) ¹⁰ or R_(G) ⁷        and R_(G) ⁸ or R_(G) ⁹ and R_(G) ¹⁰ together are an optionally        substituted, saturated or unsaturated, nonaromatic, 3 to        7-membered carbocycle or heterocycle which can contain up to 3        heteroatoms selected from the group O, N, S and up to two double        bonds,    -   R_(G) ¹¹ is hydrogen, a branched or unbranched, optionally        substituted C₁-C₈-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,        C₁-C₅-alkylene-C₁-C₄-alkoxy, mono- and bis-alkylaminoalkylene or        acylaminoalkylen radical or an optionally substituted aryl,        heterocycloalkyl, heterocycloalkenyl, hetaryl, C₃-C₇-cycloalkyl,        C₁-C₄-alkylene-C₃-C.s-ub.7-cycloalkyl, arylalkyl,        C₁-C₄-alkyleneheterocycloalkyl, C₁-C₄-alkyleneheterocycloalkenyl        or hetarylalkyl radical,    -   R_(G) ¹², R_(G) ¹³    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₈-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₅-alkylen-e-C₁-C₄-alkoxy, mono- and        bis-alkylaminoalkylene or acylaminoalkylene radical or an        optionally substituted aryl, heterocycloalkyl,        heterocycloalkenyl, hetaryl, C₃-C₇cycloalkyl-,        C₁-C₄-alkylene-C₃-C₇-cycloalkyl, arylalkyl,        C₁-C₄-alkyleneheterocycloalkyl,        C₁-C₄-alkyleneheteroc-ycloalkenyl or hetaryalkyl radical, or a        radical —SO₂—R_(G) ¹¹, —CO—OR_(G) ¹¹, —CO—NR_(G) ¹¹R_(G) ¹¹* or        —CO-R_(G) ¹¹ or both radicals R_(G) ¹² and R_(G) ¹³ together        form a 5-to 7-membered nitrogen-containing carbocycle and    -   R_(G) ¹¹ is a radical R_(G) ¹¹ which is independent of R_(G) ¹¹    -   B is a structural element containing at least one atom which,        under physiological conditions, as a hydrogen acceptor can form        hydrogen bridges, where at least one hydrogen acceptor atom has        a distance of 4 to 15 atom bonds to structural element G along        the shortest possible route along the structural element        skeleton,    -   and the physiologically tolerable salts, prodrugs and the        enantiomerically pure or diastereomerically pure and tautomeric        forms.

In the structural element L, T is understood as meaning a group COOH, aradical hydrolyzable to COOH or a radical bioisosteric to COOH.

A radical hydrolyzable to COOH is understood as meaning a radical withchanges into a group COOH after hydrolysis.

A group which may be mentioned by way of example as a radicalhydrolyzable to COOH is

-   -   in which R_(T) ¹ has the following meanings:    -   a) OM, where M can be a metal cation, such as an alkali metal        cation, such as lithium, sodium, potassium, the equivalent of an        alkaline earth metal cation, such as calcium, magnesium and        barium, or an environmentally tolerable organic ammonium ion        such as primary, secondary, tertiary or quaternary        C₁-C₄-alkylammonium or ammonium ion, such as ONa, OK or OLi,    -   b) a branched or unbranched, optionally halogen-substituted        C₁-C₈-alkoxy radical, such as methoxy, ethoxy, propoxy,        1-methylethoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy        1,1-dimethylethoxy, in particular methoxy, ethoxy,        1-methylethoxy, pentoxy, hexoxy, heptoxy, octoxy,        difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy,        1-fluoroethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy,        1,1,2,2-tetrafluoroethoxy, 2,2,2-trifluoroethoxy,        2-chloro-1,1,2-trifluoroethoxy or pentafluoroethoxy,    -   c) a branched or unbranched, optionally halogen-substituted        C₁-C₄-alkylthio radical such as methylthio, ethylthio,        propylthio, 1 -methylethylthio, butylthio, 1-methylpropylthio,        2-methylpropylthio or 1,1-dimethylethylthio radical,    -   d) an optionally substituted —O-alkylenearyl radical, such as        —O-benzyl,    -   e) R_(T) ¹ is further a radical —(O)_(m)—N(R¹⁸)(R¹⁹), in which m        is 0 or 1 and R¹⁸ and R¹⁹, which can be identical or different,        have the following meanings:    -   hydrogen,    -   a branched or unbranched, optionally substituted    -   C₁-C₆-alkyl radical, such as methyl, ethyl, propyl, 1        -methylethyl, butyl, 1-methylpropyl, 2-methylpropyl,        1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,        1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,        1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl,        1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl        2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,        1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or 1        -ethyl-2-methylpropyl or the corresponding substituted radicals,        preferably methyl, ethyl, propyl, butyl or i-butyl,    -   C₂-C₆-alkenyl radical, such as vinyl, 2-propenyl, 2-butenyl,        3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl,        2-pententyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl,        2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-methyl-3-butenyl,        2-methyl-3-butenyl, 3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl,        1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl, 2-hexenyl,        3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,        2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,        3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,        2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl,        1,1-dimethyl-2 -butenyl, 1,1-dimethyl-3-butenyl,        1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,        1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,        2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl,        2,3-dimethyl-3-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,        2-ethyl-2-butenyl, 2-ethyl-3-butenyl,        1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl and        1-ethyl-2-methyl-2-propenyl, in particular 2-propenyl,        2-butenyl, 3-methyl-2-butenyl or 3-methyl-2-pentenyl or the        corresponding substituted radicals,    -   C₂-C₆-alkynyl radical, such as ethynyl, 2-propynyl, 2-butynyl,        3-butynyl, 1-methyl-2propynyl, 2-pentynyl, 3-pentynyl,        4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl,        1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl,        2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl,        1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,        2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl,        4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,        1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,        2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,        2-ethyl-3--butynyl and 1-ethyl-1-methyl-2-propynyl, preferably        2-propynyl 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl        or the corresponding substituted radicals,    -   C₃-C₈-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl and cycloheptyl, cyclooctyl or the corresponding        substituted radicals,    -   or a phenyl radical, optionally mono- or polysubstituted, for        example mono- to trisubstituted, by halogen, nitro, cyano,        C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy or        C₁-C₄-alkylthio such as 2-fluorophenyl, 3-chlorophenyl,        4-bromophenyl, 2-methylphenyl, 3-nitrophenyl, 4-cyanophenyl,        2-trifluoromethylphenyl, 3-methoxyphenyl,        4-trifluoroethoxyphenyl, 2-methylthiphenyl, 2,4-dichlorophenyl,        2-methoxy-3-methylphenyl, 2,4-dimethoxyphenyl,        2-nitro-5-cyanophenyl, 2,6-difluorophenyl,    -   or R¹⁸ and R¹⁹ together form an optionally substituted, e.g.        C₁-C₄-alkyl-substituted, C₄-C7-alkylene chain closed to give a        cycle which can contain a heteroatom selected from the group        consisting of oxygen, sulfur and nitrogen, such as —(CH₂)₄—,        —(CH₂)₅—, —(CH₂)₆—, —(CH₂)₇—, —(CH₂)₂—O—(CH₂)₂—, —CH₂—S—(CH₂)₃—,        —(CH₂)₂—O—(CH₂)₃—, —NH—(CH₂)₃—, —CH₂—NH—(CH₂)₂—,        —CH₂—CH.═CH—CH₂—, —CH═CH—(CH₂)₃—, —CO—(CH₂)₂—CO— or        —CO—(CH₂)₃—CO—.

A radical biolsosteric to COOH is understood as meaning radicals whichcan replace the function of a group COOH in active compounds byequivalent bond donor/acceptor capabilities or by equivalent chargedistribution.

Radicals which may be mentioned by way of example as radicalsbioisosteric to —COOH are those such as described in “The Practice ofMedicinal Chemistry, Editor: C. G. Wermuth, Academic Press 1996, pages125 and 216, in particular the radicals —P═O(OH)₂, —SO₃H, tetrazole oracylsulfonamides.

Preferred radicals T are —COOH, —CO—O—C₁-C₈-alkyl or —CO—O-benzyl.

The radical —U— in the structural element L is a spacer selected fromthe group —(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, —CR_(L) ¹═CR_(L) ²—,ethynylene or 40═CR_(L) ¹—. In the case of the radical ═CR_(L) ¹—, thestructural element L is linked to the structural element G via a doublebond.

X_(L) is a radical CR_(L) ³R_(L) ⁴, NR_(L) ⁵, oxygen or sulfur.

Preferred radicals —U— are the radicals —CR_(L) ¹═CR.s-ub.L²—,ethynylene or (X_(L))_(a)—(CR_(L) ¹R_(L) ²)-_(b)—, where X_(L) ispreferably CR_(L) ³R_(L) ⁴ (a=0 or 1) or oxygen (a=1).

Particularly preferred radicals —U— are the radicals—(X_(L))_(a)—(CR_(L) ¹R_(L) ²)_(b)—, where X_(L) is preferably CR_(L)³R_(L) ⁴ (a=0 or 1) or oxygen (a=1).

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, ahalogen radical is understood as meaning, for example, F, Cl, Br or I,preferably F.

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, abranched or unbranched C₁-C₆-alkyl radical is understood as meaning, forexample, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl,1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1-methylpentyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 1,1-dimethylbutyl,2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethylbutyl, 2-ethylbutyl or1-ethyl-2-methylpropyl, preferably branched or unbranched C₁-C₄-alkylradicals such as methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, particularlypreferably methyl.

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, abranched or unbranhced C₂-C₆-alkenyl radical is understood as meaning,for example, vinyl, 2-propenyl, 2-butenyl, 3-butenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl 2-pentenyl, 3-pentenyl,4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-2-propenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-2-pentenyl,2-methyl-2-pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl,3-methyl-3-pentenyl, 4-methyl-3-pentenyl, 1-methyl-4-pentenyl,2-methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,1-ethyl-1-methyl-2-propenyl and 1-ethyl-2-methyl-2-propenyl, inparticular 2-propenyl, 2-butenyl, 3-methyl-2-butenyl or3-methyl-2-pentenyl.

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, abranched or unbranched C₂-C₆-alkynyl radical is understood as meaning,for example, ethynyl, 2-propynyl, 2-butynyl, 3-butynyl,1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl,1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-methyl-2-butynyl,1,1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, 1-methyl-2-pentynyl,1-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl,2-methyl-4-pentynyl, 3-methyl-4-pentynyl, 4-methyl-2-pentynyl,1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-3-butynyl,2,2-dimethyl-3-butynyl, 1-ethyl-2-butynyl, 1-ethyl-3-butynyl,2-ethyl-3-butynyl and 1-ethyl-1-methyl-2-propryl, preferably ethynyl,2-propynyl, 2-butynyl, 1-methyl-2-propynyl or 1-methyl-2-butynyl.

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, abranched or unbranched C₃-C₇cycloal-kyl radical is understood asmeaning, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl.

Under R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ in structural element L, abranched or unbranched C₁-C₄-alkoxy radical is understood as meaning,for example, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy,1-methylpropoxy, 2-methylpropoxy or 1,1-dimethylethoxy.

The radicals —CO—NH(C₁-C₆-alkyl), —CO—N(C₁-C₆-alkyl)₂ are secondary ortertiary amides and are composed of the amide bond and the correspondingC₁-C₆-alkyl radicals such as described above for R_(L) ¹, R_(L) ², R_(L)³ or R_(L) ⁴.

The radicals R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ can furthermore be aradical

C₁-C₂alkylene-T, such as methylene-T or ethylene-T, C2-alkenylene-T,such as ethenylene-T or C₂-alkynylene-T, such as ethynylene-T,

-   -   an aryl radical, such as phenyl, 1-naphthyl or 2-naphthyl or    -   an arylalkyl radical, such as benzyl or ethylenephenyl        (homobenzyl),    -   where the radicals can optionally be substituted.

Furthermore, two radicals R_(L) ¹ and R_(L) ² or R_(L) ³ and R_(L) ⁴ oroptionally R_(L) ¹ and R_(L) ³ can in each case independently of oneanother together be an optionally substituted 3- to 7-membered saturatedor unsaturated carbocycle or heterocycle, which can contain up to threedifferent or identical heteroatoms O, N, S.

All radicals for R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ can be optionallysubstituted. For the radicals R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ andall further substituted radicals of the description below, suitablesubstituents, if the substituents are not specified in greater detail,are independently of one another up to 5 substituents, for exampleselected from the following group:

-   -   —NO₂, —NH₂, —OH, —CN, —COOH, —O—CH₂—COOH, halogen, a branched or        unbranched, optionally substituted C₁-C₄-alkyl radical, such as        methyl, CF₃, C₂F₅ or CH₂F, —CO—O—C₁-C₄-alkyl, C₃-C₆-cycloalkyl,        C₁-C₄-alkoxy, C₁-C₄-thioalkyl, —NH—CO—O—C₁-C₄-alkyl,        —O—CH₂—COO—C₁-C₄-a-lkyl, —NH—CO—C₁-C₄-alkyl, —CO—NH—C₁-C₄-alkyl,        —NH—SO₂—C₁-C₄-alkyl, —SO₂—NH—C₁-C₄-al-kyl, —N(C₁-C₄-alkyl)₂,        20-NH—C₁-C₄-alkyl, or —SO₂—C₁-C₄-alkyl radical, such as        —SO₂—CF₃, an optionally substituted —NH—CO-aryl, —CO—NH-aryl,        —NH—CO—O-aryl, —NH—CO—O-alkylenearyl, —NH—SO₂-aryl,        —SO₂—NH-aryl, —CO—NH-benzyl, —NH—SO₂-benzyl or —SO₂—NH-benzyl        radical, an optionally substituted radical —SO₂—NR⁵ ²R⁵ ³ or        —CO—NR⁵ ²RS³ where the radicals R² and R³ independently of one        another can have the meaning R_(L) ⁵ as below or both radicals        R² and R³ together can be a 3- to 6-membered, optionally        substituted, saturated, unsaturated or aromatic heterocycle        which, in addition to the ring nitrogen, can contain up to three        further different or identical heteroatorns O, N, S, and        optionally two radicals substituted on this heterocycle can        together be a fused, saturated, unsaturated or aromatic        carbocycle or heterocycle which can contain up to three        different or identical heteroatoms O, N, S and the cycle can be        optionally substituted or a further, optionally substituted        cycle can be fused to this cycle.

If not specified in greater detail, in all terminally bonded,substituted hetaryl radicals of the description, two substituents canform a fused 5- to 7-membered, unsaturated or aromatic carbocycle.

Preferred radicals R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ areindependently of one another hydrogen, halogen, a branched orunbranched, optionally substituted C₁-C₄-alkyl, C₁-C₄-alkoxy orC₃-C₇-cycloalkyl radical or the radical —NR_(L) ⁶R_(L) ⁷.

Particularly preferred radicals R_(L) ¹, R_(L) ², R_(L) ³ or R_(L) ⁴ areindependently of one another hydrogen, fluorine or a branched orunbranched, optionally substituted C₁-C₄-alkyl radical, preferablymethyl.

The radicals R_(L) ⁵, R_(L) ⁶, R_(L) ⁷ in structural element L areindependently of one another hydrogen, a branched or unbranched,optionally substituted

-   -   C₁-C₆-alkyl radical, for example as described above for R_(L) ¹,    -   C₃-C₇-cycloalkyl radical, for example as described above for        R_(L) ¹,    -   CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl or CO—C₁-C₆-alkyl radical,        which is composed of the group CO—O, SO₂ or CO and, for example,        of the C₁-C₆-alkyl radicals described above for R_(L) ¹,    -   or an optionally substituted CO—O—-alkylenearyl, SO₂-aryl,        SO₂-alkylenearyl or CO-alkylenearyl radical, which is composed        of the group CO—O, SO₂ or CO and, for example, of the aryl or        arylalkyl radicals described above for R_(L) ¹.

Preferred radicals for R_(L) ⁶ in structural element L are hydrogen, abranched or unbranched, optionally substituted C₁-C₄-alkyl,CO—O—C₁-C₄-alkyl, CO—C₁-C₄-alkyl or SO₂—C₁-C₄-alkyl radical or anoptionally substituted Co-O-benzyl, SO₂-aryl, SO₂-alkylenearyl orCO-aryl radical.

Preferred radicals for R_(L) ⁷ in structural element L are hydrogen or abranched or unbranched, optionally substituted C₁-C₄-alkyl radical.

Preferred structural elements L are composed of the preferred radicalsof the structural element.

Particularly preferred structural elements L are composed of theparticularly preferred radicals of the structural element.

G is a structural element of the formula I_(G)

-   -   where the incorporation of the structural element G can take        place in both orientations. Preferably, the incorporation of the        structural element G into the compounds of the formula I can        take place such that the structural element B is bonded via the        ring nitrogen and the structural element L is bonded via W_(G)        to the structural element G, optionally via a double bond.

Y_(G) in structural element G is CO, CS, C═NR_(G) ² or CR_(G) ³R_(G) ⁴,preferably CO, C═NR_(G) ² or CR_(G) ³R_(G) ⁴, particularly preferably COor CR_(G) ³R_(G) ⁴.

R_(G) ² in structural element G is hydrogen, a hydroxyl group, abranched or unbranched, optionally substituted C₁-C₆-alkyl, C₁-C₄-alkoxyor C₃-C₇-cycloalk- yl radical, for example as described above for R_(L)¹ in each case,

-   -   an optionally substituted —O—C₃-C₇-cycloalkyl radical, which is        composed of an ether group and, for example, of the        C₃-C₇-cycloalkyl radical described above for R_(L) ¹,    -   an optionally substituted aryl or arylalkyl radical, for example        as described above for R_(L) ¹ in each ease or    -   an optionally substituted —O—aryl or —O-alkylenearyl radical,        which is composed of a group —O— and, for example, of the aryl        or arylalkyl radicals described above for R_(L) ¹.

Preferred radicals R_(G) ² in structural element G are hydrogen,hydroxyl or a branched or unhranched, optionally substituted C₁-C₆-alkylradical, in particular methyl or C₁-C₄-alkoxy radical, in particularmethoxy.

Branched or unbranched, optionally substituted C₁-C₆-alkyl,C2-C6-alkynyl or C₁-C₄-alkoxy radicals for R_(G) ³ or R_(G) ⁴ instructural element G independently of one another are understood asmeaning, for example, the corresponding radicals in each case describedabove for R_(L) ¹.

Further, both radicals R_(G) ³ and R_(G) ⁴ can together form a cyclicacetal, such as —O—CH₂—CH₂—O— or —O—CH₂—O—.

Furthermore, both radicals R_(G) ³ and R_(G) ⁴ can together form anoptionally substituted C₃-C₇-cycloalkyl radical.

Preferred radicals for R_(G) ³ or R_(G) ⁴ are independently of oneanother hydrogen, C₁-C₆-alkyl or C₁-C₄-alkoxy, and both radicals R_(G) ³and R_(G) ⁴ together form a cyclic acetal, such as —O—CH₂—CH₂—O— or—O—CH₂—O—. Particularly preferred radicals R_(G) ³ or R_(G) ⁴ areindependently of one another hydrogen and both radicals R_(G) ³ andR_(G) ⁴ together form a cyclic acetal, in particular —O—CH₂—CH₂—O— or—O—CH₂—O—.

Branched or unbranched, optionally substituted C₁-C₆-alkyl orC₁-C₄-alkoxy radicals and optionally substituted aryl or arylalkylradicals for R_(G) ⁵ and R_(G) ⁶ in structural element G independentlyof one another are, for example, the corresponding radicals in each casedescribed above for R_(L) ¹.

Further, both radicals R_(G) ⁵ and R_(G) ⁶ can together form anoptionally substituted, fused, unsaturated or aromatic 3- to 10-memberedcarbocycle or heterocycle, which can contain up to three different oridentical heteroatoms O, N, S, where in this fused, unsaturated oraromatic 3- to 10-membered carbocycle or heterocycle, as substituents,independently of one another up to four substituents from the group

-   -   hydroxyl, halogen, such as F or Cl or a branched or unbranched,        optionally halogen-substituted C₁-C₄-alkoxy radical, such as        methoxy, C₁-C₄-thioalkyl or C₁-C₄-alkyl radical, such as methyl,        ethyl, propyl or butyl, or an optionally halogen-substituted        aryl radical, such as phenyl, hetaryl, such as described below        for RG⁷, or C₃-C₇-cycloalkyl radical, such as described below        for R_(G) ⁷, or an optionally halogen-substituted radical        —SO₂—C₁-C₄-alkyl, —SO—C₁-C₄-alkyl, —SO₂—C₁-C₄-alkylenearyl,        —SO—C₁-C₄-alkylenea- ryl, —SO₂-aryl or —SO-aryl are selected.

Preferred substituents are halogen, a C₁-C₄-alkyl radical, C₁-C₄-alkoxyradical or aryl radical.

Particularly preferred substituents are a C₁-C₄-alkyl radical, inparticular methyl or ethyl, a C₁-C₄-alkoxy radical, in particularmethoxy, or F or Cl.

Preferred radicals for R_(G) ⁵ and R_(G) ⁶ are independently of oneanother hydrogen, an optionally substituted C₁-C₆-alkyl radical, inparticular methyl and ethyl, an optionally substituted aryl radical, inparticular optionally substituted phenyl or an optionally substitutedarylalkyl radical, in particular an optionally substituted benzylradical, and in each case both radicals R_(G) ⁵ and R_(G) ⁶ together canbe an optionally substituted, fused, unsaturated or aromatic 3- to10-membered carbocycle or heterocycle which can contain up to threedifferent or identical heteroatoms O, N, S.

In particularly preferred radicals for R_(G) ⁵ and R_(G) ⁶, bothradicals R_(G) ⁵ and R_(G) ⁶ together form an optionally substituted,fused, unsaturated or aromatic 3- to 6-membered carbocycle orheterocycle, for example selected from one of the following doublybonded structural formulae:

-   -   in particular selected from one of the following, doubly bonded        structural formulae:

W_(G) is a structural element selected from the group of structuralelements of the formulae I_(WG) ¹ to I_(WG) ⁴, where the dashed linesintersect the atomic bonds within the structural element G and thecarbon atom substituted by R_(G) ⁷ and R_(G) ⁸ is bonded to Y_(G).

In a preferred embodiment, W_(G) is a structural element selected fromthe group of structural elements of the formulae I_(WG) ¹, I_(WG) ² andI_(WG) ⁴, in particular the structural element of the formula IWG².

R_(G) ¹ in structural element W_(G) is hydrogen, halogen, such as Cl, F,Br or I, a hydroxyl group or a branched or unbranched, optionallysubstituted C₁-C₆-alkyl radical, preferably C₁-C₄-alkyl or C₁-C₄-alkoxyradical such as in each case described above for R_(L) ¹.

Preferred radicals for R_(G) ¹ are hydrogen, hydroxyl and optionallysubstituted C₁-C₄-alkyl or C₁-C₄-alkoxy radicals.

Particularly preferred radicals for R_(G) ¹ are hydrogen andcarboxyl-substituted C₁-C₄-alkyl or C₁-C₄-alkoxy radicals, in particularthe radicals —CH₂COOH or —O—CH₂COOH.

R_(G) ⁷, R_(G) ⁸, R_(G) ⁹ and R_(G) ¹⁰ in structural element G areindependently of one another hydrogen, a hydroxyl group, CN, halogen,such as F, Cl, Br, I, a branched or unbranched, optionally substituted

-   -   C₁-C₆-alkyl radical, such as optionally substituted methyl,        ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl,        2-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,        2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl,        1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,        1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl,        1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethylbutyl,        2-ethylbutyl or 1-ethyl-2-methylpropyl,    -   C₂-C₆-alkenyl radical, such as optionally substituted vinyl,        2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl,        2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,        1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,        1-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,        1,1-dimethyl-2-propenyl, 1,2-dimethyl-2-propenyl,        1-ethyl-2-propenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,        1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentenyl,        4-methyl-2-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,        1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,        4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,        1,1-dimethyl-3-butenyl, 1,2-dimethyl-2-butenyl,        1,2-dimethyl-3-butenyl, 1,3-dimethyl-2-butenyl,        1,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl,        2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,        1-ethyl-2-butenyl, 1-ethyl-3-butenyl, 2-ethyl-2-butenyl,        2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl,        1-ethyl-1-methyl-2-propeny-1 or 1-ethyl-2-methyl-2-propenyl,    -   C₂-C₆-alkynyl radical, such as optionally substituted ethynyl,        2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl,        2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl,        2-methyl-3-butynyl, 1-methyl-2-butynyl, 1,1-dimethyl-2-propynyl,        1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl,        1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 1-methyl-4-pentynyl,        2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-4-pentynyl,        4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl,        1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl,        1,2-dimethyl-3-butynyl, 2,2-dimethyl-3-butynyl,        1-ethyl-2-butynyl, 1-ethyl-3-butynyl, 2-ethyl-3-butynyl or        1-ethyl-1-methyl-2-propynyl,        an optionally substituted    -   C₃-C₇-cycloalkyl radical, such as optionally substituted        cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,    -   C₃-C₇-heterocycloalkyl radical, such as optionally substituted        aziridinyl, diaziridinyl, oxiranyl, oxaziridinyl, oxetanyl,        thiiranyl, thietanyl, pyrrolidinyl, piperazinyl, morpholinyl,        piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl,        hexahydroazepinyl, oxepanyl, 1,2-oxathiolanyl or oxazolidinyl,    -   C₃-C₇-heterocycloalkenyl radical, such as optionally substituted        azirinyl, diazirinyl, thiirenyl, thietyl, pyrrolinyls,        oxazolinyls, azepinyl, oxepinyl, α-pyranyl, β-pyranyl,        γ-pyranyl, dihydropyranyls, 2,5-dihydropyrrolinyl or        4,5-dihydrooxazolyl, a branched or unbranched, optionally        substituted C₁-C₄-alkylene-C₃-C₇-cycloalkyl radical, which is        composed, for example, of branched or unbranched C₁-C₄-alkylene        radicals such as methylene, ethylene, propylene, n-butylene,        isobutylene or t-butylene and, for example, the above mentioned        C₃-C₇-cycloalkyl radicals,    -   a branched or unbranched optionally substituted        C₁-C₄-alkylene-C₃-C₇-heterocycloalkyl or        C₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl radical, which is        composed of optionally substituted C₁-C₄-alkylene radicals, such        as methylene, ethylene, propylene, n-butylene, isobutylene or        t-butylene and, for example, the above-mentioned        C₃-C₇-heterocycloalkyl or C₃-C₇-heterocycloalkenyl radicals, the        radicals being preferred which in the cyclic moiety contain one        or two heteroatoms selected from the group consisting of N, O        and S and up to two double bonds,    -   a branched or unbranched, optionally substituted radical        C₁-C₄-alkylene-O-R_(G) ¹¹, C₁-C₄-alkylene-CO-OR-G¹¹,        C₁-C₄-alkylene-O—CO-R_(G) ¹¹, C₁-C₄-alkylene-CO-R_(G) ¹¹,        C₁-C₄-alkylene-SO₂—NR_(G) ¹²R_(G) ¹³, C₁-C₄-alkylene-CO—NR_(G)        ¹², R_(G) ³, C₁-C₄-alkylene-O—CO—NR_(G) ¹²R_(G) ¹³,        C₁-C₄-alkylene-NR_(G) ¹²R_(G) ¹³, C₁-C₄-alkylene-SR_(G) ¹¹ or        C₁-C₄-alkylene-SO—R_(G) ¹¹ which is composed of branched or        unbranched, optionally substituted C₁-C₄-alkylene radicals, such        as methylene, ethylene, propylene, n-butylene, isobutylene or        t-butylene, the corresponding groups —O—, —CO—, —S—, —N and the        terminal radicals R_(G) ¹¹, R_(G) ¹² and R_(G) ¹³ described        below,        an optionally substituted    -   aryl radical, preferably optionally substituted phenyl,        1-naphthyl or 2-naphthyl,    -   arylalkyl radical, preferably optionally substituted benzyl or        ethylenephenyl (homobenzyl),    -   hetaryl radical, preferably optionally substituted 2-pyridyl,        3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,        2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,        2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl,        5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,        3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl,        4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl,        5-pyridazinyl, 6-pyridazinyl, 3-isoxazolyl, 4-isoxazolyl,        5-isoxazolyl, thiadiazolyl, oxadiazolyl or triazinyl or their        fused derivatives such as indazolyl, indolyl, benzothiophenyl,        benzofuranyl, indolinyl, benzimidazolyl, benzothiazolyl,        benzoxazolyl, quinolinyl or isoquinolinyl,    -   hetarylalkyl radical, preferably optionally substituted        —CH₂-2-pyridyl, —CH₂-3-pyridyl, —CH₂-4-pyridyl, —CH₂-2-thienyl,        —CH₂-3-thienyl, —CH₂-2-thiazolyl, —CH₂-4-thiazolyl,        —CH₂-5-thiazolyl, —CH₂—CH₂-2-py- ridyl, —CH₂—CH₂-3-pyridyl,        —CH₂—CH₂-4-pyridyl, —CH₂—CH₂-2-thienyl, —CH₂—CH₂-3-thienyl,        10-CH₂—CH₂-2-thiazolyl, —CH₂—CH₂-4-thiazolyl or        —CH₂—CH₂-5-thiazolyl or    -   a radical —S—R¹¹, —O—R_(G) ¹¹, —SO-R_(G) ¹¹, —SO₂—R_(G) ¹¹,        —CO—OR_(G) ¹¹, —O—CO-R_(G) ¹¹, —O—CO—NR_(G) ¹²R_(G) ¹³,        —SO₂—NR_(G) ¹²R_(G) ¹³, —CO—NR_(G) ¹²R_(G) ¹³, —NR_(G) ¹²R_(G)        ¹³, CO—R_(G) ¹¹.

Further, two radicals R_(G) ⁷ and R_(G) ⁹ or R_(G) ⁸ and R_(G) ¹⁰ orR_(G) ⁷ and R_(G) ⁸ or R_(G) ⁹ and R_(G) ¹O can in each caseindependently of one another together form an optionally substituted,saturated or unsaturated, nonaromatic, 3- to 7-membered carbocycle orheterocycle which can contain up to 3 heteroatoms selected from thegroup consisting of O, N, S and up to two double bonds.

Preferred radicals for R_(G) ⁷, R_(G) ⁸, R_(G) ⁹ and R_(G) ¹⁰ in thestructural element G are independently of one another hydrogen, halogen,in particular a branched or unbranched, optionally substitutedC₁-C₆-alkyl, or C₂-C₆-alkynyl radical, a branched or unbranched,optionally substituted radical C₁-C₄-alkylene-OR_(G) ¹¹,C₁-C₄-alkylene-CO—OR-_(G) ¹¹, C₁-C₄-alkylene-O—CO-R_(G) ¹¹,C₁-C₄-alkylene-CO—NR_(G) ¹²R_(G) ¹³, C₁-C₄-alkylene-O—CO—NR_(G) ¹²R_(G)¹³, a radical —O-R_(G) ¹¹, —CO—OR_(G) ¹¹, —O—CO—R_(G) ¹¹, —O—CO—NR_(G)¹²R_(G) ¹³, —CO—NR_(G) ¹²R_(G)-13, —NR_(G) ¹²R_(G) ¹³ or CO—R_(G) ¹¹, anoptionally substituted aryl, hetaryl or arylalkyl radical, as describedabove in each case.

Particularly preferred radicals for R_(G) ⁷ R_(G) ⁸, R_(G) ⁹ and R_(G)¹⁰ in the structural element G are independently of one anotherhydrogen, F, a radical —CO—OR_(G) ¹¹, —CO—NR_(G) ¹²R_(G) ¹³, or anoptionally substituted aryl radical, as described above in each case.

A branched or unbranched, optionally substituted C₁-C₈-alkyl radical forR_(G) ¹¹, R_(G) ¹² and R_(G) ¹³ is understood as meaning independentlyof one another, for example, the C₁-C₆-alkyl radicals mentioned abovefor R_(G) ¹, plus the radicals heptyl and octyl.

Preferred substituents of the branched or unbranched, optionallysubstituted C₁-C₈-alkyl radicals for R_(G) ¹¹, R_(G) ¹² and R_(G) ¹³independently of one another are the radicals halogen, hydroxyl,C₁-C₄-alkoxy, —CN, —COOH and —CO—O—C₁-C₄-alkyl.

A branched or unbranched, optionally substituted C₂-C₆-alkenyl,C₂-C₆-alkynyl or C₁-C₄-alkylene-C₃-C₇-cycloalkyl radical, an optionallysubstituted C₃-C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkylradical for R_(G) ¹¹, R_(G) ¹² and R_(G) ¹³ independently of one anotheris understood as meaning, for example, the corresponding radicalsmentioned above for R_(G) ¹.

Preferred branched or unbranched, optionally substituted—C₁-C₅-alkylene-C₁-C₄-alkoxy radicals for R_(G) ¹¹, R_(G) ¹² and R_(G)¹³ are independently of one another methoxymethylene, ethoxymethylene,t-butoxymethylene, methoxyethylene or ethoxyethylene.

Preferred branched or unbranched, optionally substituted mono- andbisalkylaminoalkylene or acylaminoalkylene radicals for R_(G) ¹¹, R_(G)¹² and R_(G) ¹³ are independently of one another branched or unbranched,optionally substituted radicals —C₁-C₄-alkylene-NH(C₁-C₄-alkyl),—C₁-C₄-alkylene-N(C₁-C₄-alkyl)₂or —C₁-C₄-alkylene-NH—CO—C₁-C₄-alkyl.

Preferred optionally substituted heterocycloalkyl, heterocycloalkenyl,C₁-C₄-alkyleneheterocycloalkyl or C₁-C₄-alkyleneheterocycloalkenylradicals for R_(G) ¹¹, R_(G) ¹² and R_(G) ¹³ are independently of oneanother the C₃-C₇-heterocycloalkyl, C₃-C₇-heterocycloalkenyl,C₁-C₄-alkylene-C₃-C₇-heterocycloalkyl orC₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl radicals described above forR_(G) ¹.

Particularly preferred, optionally substituted heterocycloalkyl,heterocycloalkenyl, C₁-C₄-alkyleneheterocycloalkyl orC₁-C₄-alkyleneheterocycloalkenyl radicals for R_(G) ¹¹, R_(G) ¹² andR_(G) ¹³ are independently of one another the C₃-C₇-heterocycloalkyl,C₃-C₇-heterocycloalkenyl, C₁-C₄--alkylene-C₃-C₇-heterocycloalkyl orC₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl radicals described above forR_(G) ¹, one or two heteroatoms being selected from the group consistingof N, O and S and up to two double bonds being contained in the cyclicmoiety.

Furher, R_(G) ¹² and R_(G) ¹³ can independently of one another be aradical —SO₂—R_(G) ¹¹, —CO—O-R_(G) ¹¹, —CO—NR_(G) ¹¹R_(G) ¹¹* or—CO-R_(G) ¹¹, R_(G) ¹¹* being a radical R_(G) ¹¹ which is independent ofR_(G) ¹¹.

Furthermore, both radicals R_(G) ¹² and R_(G) ¹³ can together form a 5-to 7-membered, preferably saturated nitrogen-containing carbocycle, inthe sense of a cyclic amine structure, such as N-pyrrolidinyl,N-piperidinyl, N-hexahydroazepinyl, N-morpholinyl or N-piperazinyl,where in the case of heterocycles which carry free amine protons, suchas N-piperazinyl, the free amine protons can be replaced by customaryamine protective groups, such as methyl, benzyl, Boc(tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO₂—C₁-C₄-alkyl,—SO₂-phenyl or —SO₂-benzyl.

Particularly preferred radicals for R_(G) ¹¹ are hydrogen or anoptionally substituted C₁-C₄-alkyl or aryl radical.

Particularly preferred for R_(G) ¹² and R_(G) ¹³ are independently ofone another hydrogen or an optionally substituted C₁-C₄-alkyl radical.

Preffered structural elements G are composed of at least one preferredradical of the strucural element G, while the remaining radicals arewidely variable.

Particularly preferred structural elements G are composed of thepreferred radicals of the structural element G.

Very particularly preferred structural elements G are composed of theparticularly preferred radicals of the structtnul element G.

Structural element B is undentood as meaning a structural elementcomprising at least one atom which under physiological conditions canform hydrogren bridges as a hydrogen acceptor, at least one hydrogenacceptor atom having a distance of 4 to 15 atom bonds to structuralelement G along the shortest possible route along the structural elementskeleton. The arrangement of the structural skeleton of structuralelement B is widely variable.

Suitable atoms which under physiological conditions can form hydrogenbridges as hydrogen acceptors are, for example, atoms having Lewis baseproperties, such as the heteroatoms nitrogen, oxygen or sulfur.

Physiological conditions is understood as meaning a pH which prevails atthe site in a body at which the ligands interact with the receptors. Inthe present case, the physiological conditions have a pH of, forexample, 5 to 9.

In a preferred embodiment, structural element B is a structural elementof the formula IB

A-E-tm IB

-   -   where A and E have the following meanings:    -   A is a structural element selected from the group:    -   a 4- to 8-membered monocyclic saturated, unsaturated or aromatic        hydrocarbon which can contain up to 4 heteroatoms selected from        the group O, N and S, where, in each case independently of one        another, the ring nitrogen optionally contained or the carbons        can be substituted, with the proviso that at least one        heteroatom selected from the group O, N and S contained in the        structural element A, or    -   a 9- to 14-membered polycyclic, saturated, unsaturated or        aromatic hydrocarbon which can contain up to 6 heteroatoms        selected from the group N, O and S, where, in each case        independently of one another, the ring nitrogen optionally        contained or the carbons can be substituted, with the proviso        that at least one heteroatom selected from the group O, N and S        is contained in the structural element A,    -   a radical

where

-   -   Z_(A) 1 is oxygen, sulfur or optionally substituted nitrogen and    -   Z_(A) 2 is optionally substituted nitrogen, oxygen or sulfur,    -   or a radical

where

-   -   RA¹⁸, R_(A) ¹⁹    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₈-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₅-alkylen-e-C₁-C₄-alkoxy, mono- and        bisalkylaminoalkylene or acylaminoalkylene radical or an        optionally substituted aryl, heterocycloalkyl,        heterocycloalkenyl, hetaryl, C₃-C₇-cycloalkyl-,        C₁-C₄-alkylene-C₃-C₇-cycloalkyl, arylalkyl,        C₁-C₄-alkyleneheterocycloalkyl, C₁-C₄-alkyleneheteroc-        ycloalkenyl or hetarylalkyl radical, or a radical —SO₂—R_(G) ¹¹,        —CO—OR_(G) ¹¹, —CO-NR¹¹R_(G) ¹¹* or —CO—R_(G) ¹¹ and    -   E is a spacer structural clement which covalentily bonds the        structural element A to the structural element G, where the        number of atom bonds along the shortest possible route along the        structural element skeleton E is 3 to 14.

In a particularly preferred embodiment, the structural element A is astructural element selected from the group of structural elements of theformulae I_(A)1 to I_(A) ¹⁸,

where

-   -   independently of one another are 1, 2 or 3,    -   independently of one another are hydrogen, CN, halogen, a        branched or unbranched, optionally substituted C₁-C₁₋₆-alkyl or        CO—C₁-C₆-alkyl radical or an optionally substituted aryl,        arylalkyl, hetaryl, hetarylalkyl or C₃-C₇-cycloalkyl radical or        a radical CO—O-R_(A) ¹⁴, O-R_(A) ¹⁴, S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A)        ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ or SO₂NR_(A) ¹⁵R_(A) ¹⁶ or both        radicals R_(A) ¹ and R_(A) ² together are a fused, optionally        substituted, 5- or 6-membered, unsaturated or aromatic        carbocycle or heterocycle which can contain up to three        heteroatoms selected from the group O, N, and S,    -   R_(A) ¹³, R_(A) ¹³*    -   independently of one another are hydrogen, CN, halogen, a        branched or unbranched, optionally substituted C₁-C₆-alkyl        radical or an optionally substituted aryl, arylalkyl, hetaryl,        C₃-C₇-cycloalk- yl radical or a radical CO—O-R_(A) ¹⁴, O-R_(A)        ¹⁴, S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, SO₂—NR_(A) ¹-5R_(A) ¹⁶ or        CO—NR_(A) ¹⁵R_(A) ¹⁶,        where    -   R_(A) ¹⁴ is hydrogen, a branched or unbranched, optionally        substituted C₁-C₆-alkyl, alkylene-C₁-C₄-alkoxy, C₂-C₆-alkenyl,        C₂-C₆-alkynyl or C₁-C₆-alkylene-C₃-C₇-cycloalkyl radical or an        optionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl,        hetaryl or hetarylalkyl radical,    -   R_(A) ¹⁵, R_(A) ¹⁶,    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl, CO—C₁-C₆-alkyl,        SO₂—C₁-C₆-alkyl, COO—C₁-C₆-alkyl, CO—NH—C₁-C₆-alkyl, arylalkyl,        COO-alkylenearyl, SO₂-alkylenearyl, CO—NH-alkylenearyl,        CO—NH-alkylenehetaryl or hetarylalkyl radical or an optionally        substituted C₃C₇-cycloalkyl, aryl, CO-aryl, CO—NH-aryl,        SO₂-aryl, hetaryl, CO—NH-hetaryl or Co-hetaryl radical,    -   R_(A) ³, R_(A) ⁴    -   independently of one another are hydrogen,        —(CH₂)_(n)—(X_(A))_(j)—R_(A) ¹², or both radicals together are a        3- to 8-membered, saturated, unsaturated or aromatic        N-heterocycle which can additionally contain two further,        identical or different heteroatoms O, N or S, where the cycle is        optionally substituted or a further, optionally substituted,        saturated, unsaturated or aromatic cycle can be fused to this        cycle,        where    -   n is 0, 1, 2 or 3,    -   j is 0 or 1,    -   X_(A) is —CO—, —CO—N(R_(x) ¹)—, —N(R_(x) ¹)-CO—, —N(R_(x)        ¹)—CO—N(R_(x) ¹*)—, —N(R_(x) ¹)—CO—O—, —O—, —S—, —SO₂—,        —SO₂—N(R_(x) ¹)—, —SO₂—O—, —CO—O—, —O—CO—, —O—CO—N(R_(x) ¹)—,        —N(R_(x) ¹)— or —N(R_(x) ¹)—SO₂—,    -   R_(A) ¹² is hydrogen, a branched or unbranched, optionally        substituted C₁-C₆-alkyl radical, an optionally C₁-C₄-alkyl- or        aryl-substituted C₂-C₆-alkynyl or C₂-C₆-alkenyl radical or a 3-        to 6-membered, saturated or unsaturated heterocycle, substituted        by up to three identical or different radicals, which can        contain up to three different or identical heteroatoms O, N, S,        a C₃-C₇-cycloalkyl, aryl or hetaryl radical, where two radicals        together can be a fused, saturated, unsaturated or aromatic        carbocycle or heterocycle which can contain up to three        different or identical heteroatoms O, N, S and the cycle can        optionally be substituted or a further, optionally substituted,        saturated, unsaturated or aromatic cycle can be fused to this        cycle, or the radical R_(A) ¹², together with RX¹ or RX1* forms        a saturated or unsaturated C₃-C₇-heterocycle which can        optionally contain up to two further heteroatoms selected from        the group O, S and N,    -   R_(x) ¹, R_(x) ¹*    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkoxyalkyl, C₂-C₆-alkenyl, C₂-C₁2-alkynyl,        CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl or SO₂—C₁-C₆-alkyl radical or        an optionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl,        CO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO₂-aryl, hetaryl,        CO-hetaryl or SO₂-alkylenearyl radical,    -   R_(A) ⁶, R_(A) ⁶*    -   are hydrogen, a branched or unbranched, optionally substituted        C₁-C₄-alkyl, —CO—O—C₁-C₄-alkyl, arylalkyl, —CO—O-alkylenearyl,        —CO—O-allyl, —CO—C₁-C₄-alkyl, —CO-alkylenearyl, C₃-C₇-cycloalkyl        or —CO-allyl radical or in structural element I_(A) ⁷ radicals        R_(A) ⁶ and R_(A) ⁶* together are an optionally substituted,        saturated, unsaturated or aromatic heterocycle which, in        addition to the ring nitrogen, can contain up to two further        different or identical heteroatoms O, N, S,    -   R_(A) ⁷ is hydrogen, —OH, —CN, —CONH₂, a branched or unbranched,        optionally substituted C₁-C₄-alkyl, C₁-C₄-alkoxy,        C₃-C₇-cycloalkyl or —O—CO—C₁-C₄-alkyl radical, or an optionally        substituted arylalkyl, —O-alkylenearyl, —O—CO-aryl,        —O—CO-alkylenearyl or radical, or both radicals R_(A) ⁶ and        R_(A) ⁷ together are an optionally substituted, unsaturated or        aromatic heterocycle which, in addition to the ring nitrogen,        can contain up to two further different or identical        heteroatorns O, N, S,    -   R_(A) ⁸ is hydrogen, a branched or unbranched, optionally        substituted C₁-C₄-alkyl, CO—C₁-C₄-alkyl, SO₂—C₁-C₄-alkyl or        CO—O—C₁-C₄-alkyl radical or an optionally substituted aryl,        CO-aryl, SO₂-aryl, CO—O-aryl, CO-alkylenearyl, SO₂-alkylenearyl,        CO—O-alkylenearyl or alkylenearyl radical,    -   R_(A) ⁹, R_(A) ¹⁰    -   independently of one another are hydrogen, —CN, halogen, a        branched or unbranched, optionally substituted C₁-C₆-alkyl        radical or an optionally substituted aryl, arylalkyl, hetaryl,        C₃-C₇-cycloalkyl radical or a radical CO-O-R_(A) ¹⁴, O-R_(A) ¹⁴,        S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, SO₂—NR_(A) ¹⁵R_(A) ¹⁶ or        CO—NR_(A) ¹⁵R_(A).sup-.16, or both radicals R_(A) ⁹ and R_(A) ¹⁰        together in structural element I_(A) ¹⁴ are a 5- to 7-membered        saturated, unsaturated or aromatic carbocycle or heterocycle        which can contain up to three different or identical heteroatoms        O, N, S and is optionally substituted by up to three identical        or different radicals,    -   R_(A) ¹¹ is hydrogen, —CN, halogen, a branched or unbranched,        optionally substituted C₁-C₆-alkyl radical or an optionally        substituted aryl, arylalkyl, hetaryl, C₃-C₇-cycloalk- yl radical        or a radical CO-o-R_(A) ¹⁴, O-R_(A) ¹⁴, S-R_(A) ¹⁴, NR_(A)        ¹⁵R_(A) ¹⁶, SO₂—NR_(A) ¹-5R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶,    -   R_(A) ¹⁷ is hydrogen o,r in structural element I_(A) ¹⁶, both        radicals R_(A) ⁹ and R_(A) ¹⁷ together are a 5 to 7-membered        saturated, unsaturated or aromatic heterocycle which, in        addition to the ring nitrogen, can contain up to three different        or identical heteroatoms O, N, S and is optionally substituted        by up to three identical or different radicals,    -   R_(A) ¹⁸, R_(A) ¹⁹    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₈-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl, C₁-C₅-alkylen- e-C₁-C₄-alkoxy, mono- and        bisalkylaminoalkylene or acylaminoalkylene radical or an        optionally substituted aryl, heterocycloalkyl,        heterocycloalkenyl, hetaryl, C₃-C₇-cycloalkyl-,        C₁-C₄-alkylene-C₃-C₇-cycloalkyl, arylalkyl,        C₁-C₄-alkyleneheterocycloalkyl, C₁-C₄-alkyleneheteroc-        ycloalkenyl or hetarylalkyl radical, or a radical —SO₂—R_(G)-        11, —CO—ORG¹¹, —CO—NR_(G) ¹¹R_(G) ¹¹* or —CO-R_(G) ¹¹ which is        independent of R_(G) ¹¹    -   Z¹, Z², Z³, Z⁴,    -   independently of one another are nitrogen, C—H, C-halogen or a        branched or unbranched optionally substituted C—C₁-C₄-alkyl or        C—C₁-C₄-alkoxy radical,    -   Z⁵ is NR_(A) ⁸, oxygen or sulfur.

In a further very particularly preferred embodiment, the structuralelement A is a structural element of the formula I_(A) ¹ I_(A) ⁴, I_(A)⁷, I_(A) ⁸ or I_(A) ⁹.

A branched or unbranched, optionally substituted C₁C₆-alkyl radical forR_(A) ¹ or R_(A) ² independently of one another is understood asmeaning, for example, the corresponding radicals described above forR_(G) ¹, preferably methyl or trifluoromethyl.

For R_(A) ¹ or R_(A) ² in the structural elements I_(A) ¹, I₂ ², I_(A) ³I_(A) ¹⁷ the branched or unbranched optionally substituted radicalCO—C₁-C₆-alkyl is composed, for example, of the group CO and thebranched or unbranched, optionally substituted C₁-C₆-alkyl radicalsdescribed above for R_(A) ¹ or R_(A) ².

Optionally substituted hetaryl, hetarylalkyl, aryl, arylalkyl orC₃C₇-cycloalkyl radicals for R_(A) ¹ or R_(A) ² independently of oneanother are understood as meaning, for example, the correspondingradicals described above for R_(G) ⁷.

For R_(A) ¹ or R_(A) ², the optionally substituted radicals Co-O-R_(A)¹⁴, O-R_(A) ¹⁴, S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, CO—NR_(A) ¹⁵R_(A) ¹⁶ orSO₂NR_(A) ¹⁵R_(A) ¹⁶ are composed, for example, of the groups CO—O, O,S, N, CO—N or SO₂—N and the radicals R_(A) ¹⁴, R_(A) ¹⁵ or R_(A) ¹⁶described in greater detail below.

Further, both radicals R_(A) ¹ and R_(A) ² can together form a fused,optionally substituted, 5- or 6-membered, unsaturated or aromaticcarbocycle or heterocycle which can contain up to three heteroatomsselected from the group consisting of O, N and S.

-   -   R_(A) ¹³ and R_(A) ¹³* are independently of one another        hydrogen, CN,    -   halogen, such as fluorine, chlorine, bromine or iodine,    -   a branched or unbranched, optionally substituted C₁-C₆-alkyl        radical, such as described above for R_(G) ¹, preferably methyl        or trifluoromethyl or    -   an optionally substituted aryl, arylalkyl, hetaryl or        C₃-C₇-cycloalkyl radical or a radical Co-O-R_(A) ¹⁴, O-R_(A) ¹⁴,        S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, SO₂NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A)        ¹⁵R_(A) ¹⁶ as in each case described above for R_(A) ¹.

Preferred radicals for R_(A) ¹³ and R_(A) ¹³* are the radicals hydrogen,F, Cl, a branched or unbranched, optionally substituted C₁-C₅-alkylradical, optionally substituted aryl or arylalkyl or a radicalCo-O-R_(A) ¹⁴, O-R_(A) ¹⁴, NR_(A) ¹⁵R_(A) ¹⁶, SO₂-NR_(A) ¹⁵R_(A) ¹⁶ orCO—NR_(A) ¹⁵R_(A) ¹⁶.

A branched or unbranched, optionally substituted C₁-C₆-alkyl,C₃-C₇-cycloalkyl, alkylenecycloalkyl, alkylene-C₁-C₄-alkoxy,C₂-C₆-alkenyl or C₂-C₆-alkynyl radical for R_(A) ¹⁴ in structuralelement A is understood as meaning, for example, the correspondingradicals described above for R_(G) ⁷.

Optionally substituted aryl, arylalkyl, hetaryl or alkylhetaryl radicalsfor R_(A) ¹⁴ in structural element A are understood as meaning, forexample, the corresponding radicals described above for R_(G) ⁷.

Preferred radicals for R_(A) ¹⁴ are hydrogen, a branched or unbranched,optionally substituted C₁-C₆-alkyl radical and optionally substitutedbenzyl.

A branched or unbranched, optionally substituted C₁-C₆-alkyl orarylalkyl radical or an optionally substituted C₃-C₇-cycloalkyl, aryl,hetaryl or hetaryalkyl radical for R_(A) ¹⁵ or R_(A) ¹⁶ independently ofone another is understood as meaning, for example, the correspondingradicals described above for R_(A) ¹⁴.

The branched or unbranched, optionally substituted CO—C₁-C₆-alkyl,SO₂—C₁-C₆-alkyl, COO-C₁-C₆-alkyl, CO—NH—C₁-C₆-alkyl, COO-alkylenearyl,CO—NH-alkylenearyl, CO—NH-alkylenehetaryl or SO₂-alkylenearyl radicalsor the optionally substituted CO-aryl, SO₂-aryl, CO—NH-aryl,CO—NH-hetaryl or CO-hetaryl radicals for R_(A) ¹⁵ or R_(A) ¹⁶ arecomposed, for example, of the corresponding groups —CO—, SO₂—, —CO—O—,—CO—NH— and the corresponding branched or unbranched optionallysubstituted C₁-C₆alkyl, hetarylalkyl or arylalkyl radicals or thecorresponding optionally substituted aryl or hetaryl radicals describedabove.

A radical —(CH₂)_(n)—(X_(A))_(j)—R_(A) ¹² for R_(A) ³ or R_(A) ⁴independently of one another is understood as meaning a radical which iscomposed of the corresponding radicals —(CH₂)_(n)—, (XA)_(j) and R_(A)¹². Here, n can be 0, 1, 2 or 3 and j can be: 0 or 1.

X_(A) is a doubly bonded radical selected from the group consisting of—CO—, —CO—N(R_(x) ¹)—, —N(R_(x) ¹)—CO—, —N((R_(x) ¹))-Co-N((R_(x) ¹)*)-,—N(Rx¹)—CO—O—, —O—, —S—, —SO₂—, —SO₂—N(R_(x) ¹)—, —SO₂—O—, —CO—O—,—O—CO—, —O—CO—N((R_(x) ¹))—, —N(Rx¹)— or —N((R_(x) ¹))—SO₂—.

-   -   R_(A) ¹² is hydrogen,    -   a branched or unbranched, optionally substituted C₁-C₆-alkyl        radical, as described above for R_(G) ⁷,    -   a C₂-C₆-alkynyl or C₂-C₆-alkenyl radical optionally substituted        by C₁-C₄-alkyl or aryl,    -   or a 3- to 6-membered, saturated or unsaturated heterocycle        which is substituted by up to three identical or different        radicals and can contain up to three different or identical        heteroatoms O, N, S, such as optionally substituted 2-pyridyl,        3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl, 3-pyrrolyl,        2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,        2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl, 4-pyrimidyl,        5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,        3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, 2-imidazolyl,        4-imidazolyl, 5-imidazolyl, 3-pyridazinyl, 4-pyridazinyl,        5-pyridazinyl, 6-pyridazinyl, 2-(1,3,4-thiadiazolyl),        2-(1,3,4)-oxadiazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl,        triazinyl.

Further, R_(A) ¹² and R_(x) ¹ or RX¹* can together form a saturated orunsaturated C₃- C₇-heterocycle which can optionally contain up to twofurther heteroatoms selected from the group consisting of O, S and N.

Preferably, the radical R_(A) ¹² together with the radical R_(x) ¹ orR_(x) ¹* forms a cyclic amine as the C₃-C₇-heterocycle in the case wherethe radicals are bonded to the same nitrogen atom, such asN-pyrrolidinyl, N-piperidinyl, N-hexahydroazeptnyl, N-morpholinyl orN-piperazinyl, where in heterocycles which carry free amine protons,such as N-piperazinyl, the free amine protons can be replaced bycustomary amine protective groups, such as methyl, benzyl, Boc(tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl, —SO₂—C₁-C₄-alkyl,—SO₂-phenyl or —SO₂-benzyl.

A branched or unbranched, optionally substituted C₁-C₆-alkyl,C₂-C₁2-alkynyl, preferably C₂-C₆-alkynyl or C₂-C₆-alkenyl radical, anoptionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl or hetarylradical for Rx¹ and R_(x) ¹* independently of one another is understoodas meaning, for example, the corresponding radicals described above forR_(G) ⁷.

Preferred branched or unbranched, optionally substitutedC₁-C₆-alkoxyalkyl for R_(x) ¹ and R_(x) ¹* are independently of oneanother methoxymethylene, ethoxymethylene, butoxymethylene,methoxyethylene or ethoxyethylene.

Preferred branched or unbranched, optionally substituted radicalsCO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, CO—O-alkylenearyl,CO-alkylenearyl, CO-aryl, SO₂-aryl, CO-hetaryl or SO₂-alkylenearyl arepreferably composed of the C₁-C₆-alkyl, arylalkyl, aryl or hetarylradicals and the radicals —CO—, —O—, —SO₂— described above.

Preferred radicals for R_(x) ¹and R_(x) ¹* are independently of oneanother hydrogen, methyl, cyclopropyl, allyl and propargyl.

-   -   R_(A) ³ and R_(A) ⁴ can further together form a 3- to 8-membered        saturated, unsaturated or aromatic N heterocycle which can        additionally contain two further, identical or different        heteroatoms O, N or S, where the cycle can be optionally        substituted or a further, optionally substituted, saturated,        unsaturated or aromatic cycle can be fused to this cycle,    -   R_(A) ⁵ is a branched or unbranched, optionally substituted        C₁-C₆-alkyl, arylalkyl, C₁-C₄-alkyl-C₃-C₇-c- ycloolkyl or        C₃-C₇-cycloalkyl radical or an optionally substituted aryl,        hetaryl, heterocycloalkyl or heterocycloalkenyl radical, such as        described above for R_(G) ⁷.    -   R_(A) ⁶ and R_(A) ⁶* are independently of one another hydrogen,        a branched or unbranched, optionally substituted    -   C₁-C₄-alkyl radical, such as optionally substituted methyl,        ethyl, propyl 1-methylethyl, butyl, 1-methylpropyl,        2-methylpropyl or 1,1-dimethylethyl,    -   —CO—O—C₁-C₄-alkyl or —CO—C₁-C₄-alkyl radical, such as composed        of the group —CO—O— or —CO— and the C₁-C₄-alkyl radicals        described above,    -   arylalkyl radical, as described above for R_(G) ⁷,    -   —CO—O-alkylenearyl or —CO-alkylenearyl radical such as composed        of the group —CO—O— or —CO— and the arylalkyl radicals described        above, —CO—O-allyl or —CO-allyl radical, or C₃-C₇-cycloalkyl        radical, such as described above for R_(G) ⁷.

Further, both radicals R_(A) ⁶ and R_(A) ⁶* in structural element I_(A)⁷ can together form an optionally substituted, saturated, unsaturated oraromatic heterocycle which, in addition to the ring nitrogen, cancontain up to two further different or identical heteratoms O, N, S.

R_(A) ⁷ is hydrogen, —OH, —CN, —CONH₂, a branched or unbranched,optionally substituted C₁-C₄-alkyl radical, for example as describedabove for R_(A) ⁶, C₁-C₄-alkoxy, arylalkyl or C₃-C₇-cycloalkyl radical,for example as described above for R_(L) ¹⁴, a branched or unbranched,optionally substituted —O—CO—C₁-C₄-alkyl radical, which is composed ofthe group —O—CO— and, for example, of the C₁-C₄-alkyl radicals mentionedabove or an optionally substituted —O-alkylenearyl, —O—CO-aryl,—O—CO-alkylenearyl or —O—CO-allyl radical which is composed of thegroups —O— or —O—CO— and, for example, of the corresponding radicalsdescribed above for R_(G) ⁷.

Further, both radicals R_(A) ⁶ and R_(A) ⁷ can together form anoptionally substituted unsaturated or aromatic heterocycle which, inaddition to the ring nitrogen, can contain up to two further differentor identical heteroatoms O, N, S.

For R_(A) ⁸ in structural element A, a branched or unbranched,optionally substituted C₁-C₄-alkyl radical or an optionally substitutedaryl or arylalkyl radical is understood as meaning, for example, thecorresponding radicals described above for R_(A) ¹⁵, where the radicalsCO—C₁-C₄-alkyl, SO₂- C₁-C₄-alkyl, CO—O—C₁-C₄-alkyl, CO-aryl, SO₂-aryl,CO—O-aryl, CO-alkylenearyl, SO₂-alkylenearyl or CO—O-alkylenearyl arecomposed analogously to the other composed radicals of the groupconsisting of CO, SO₂ and COO and for example, of the correspondingC₁-C₄-alkyl, aryl or arylalkyl radicals described above for R_(A) ¹⁵,and these radicals can be optionally substituted.

In each case, for R_(A) ⁹ or R_(A) ¹⁰, a branched or unbranched,optionally substituted C₁-C₆-alkyl radical or an optionally substitutedaryl, arylalkyl, hetaryl or C₃-C₇-cycloalkyl radical independently ofone another is understood as meaning, for example, the correspondingradicals described above for R_(A) ¹⁴, preferably methyl ortrifluoromethyl.

In each case, for R_(A) ⁹ or R_(A) ¹⁰, a radical CO—O—R_(A) ¹⁴, O—R_(A)¹⁴, S-R_(A) ¹⁴, SO₂—NR_(A) ¹⁵R_(A) ¹⁶, NR_(A) ¹⁵R_(A) ¹⁶or CO—NR_(A)¹⁵R_(A) ¹⁶ independently of one another is understood as meaning, forexample, the corresponding radicals described above for R_(A) ¹³.

Further, both radicals R_(A) ⁹ and R_(A) ¹⁰ together in structuralelement I_(A) ¹⁴ can form a 5- to 7-membered saturated, unsaturated oraromatic carbocycle or heterocycle, which can contain up to threedifferent or identical heteroatoms O, N, S and is optionally substitutedby up to three identical or different radicals.

Substituents in this case are in particular understood as meaninghalogen, CN, a branched or unbranched, optionally substitutedC₁-C₄-alkyl radical, such as methyl or trifluoromethyl or the radicalsO—R_(A) ¹⁴, S-R_(A) ¹⁴, NR_(A) ¹⁵R_(A)- 16, CO—NR_(A) ¹⁵R_(A) ¹⁶ or—((R_(A) ⁸)HN)C═NR.sub- .A⁷.

A branched or unbranched, optionally substituted C₁-C₆-alkyl radical oran optionally substituted aryl, arylalkyl, hetaryl, C₃-C₇-cycloalkylradical or a radical CO—O—R_(A) ¹⁴, O—R_(A) ¹⁴, S—R_(A) ¹⁴, NR_(A)¹⁵R_(A) ¹⁶, SO₂—NR_(A) ¹⁵R_(A) ¹⁶ or CO—NR_(A) ¹⁵R_(A) ¹⁶ for R_(A) ¹¹is understood, for example, as meaning the corresponding radicalsdescribed above for R_(A) ⁹.

Further, in structural element I_(A) ¹⁶, both radicals R_(A) ⁹ and R_(A)¹⁷ together can form a 5- to 7-membered saturated, unsaturated oraromatic heterocycle which, in addition to the ring nitrogen, cancontain up to three different or identical heteroatoms O, N, S and isoptionally substituted by up to three identical or different radicals.

A branched or unbranched, optionally substituted C₁-C₈-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₅-alkylene-C₁-C₄-alkoxy, mono- andbisalkylaminoalkylene or acylaminoalkylene radical or an optionallysubstituted aryl, heterocycloalkyl, heteroeycloalkenyl, hetaryl,C₃-C₇-cycloalkyl, C₁-C₄-alkylene-C₃-C₇-cycl- oalkyl, arylalkyl,C₁-C₄-alkyleneheterocycloalkyl, C₁-C₄-alkyleneheterocycloalkenyl orhetarylalkyl radical, or a radical —SO₂—R_(G) ¹¹, —CO—OR_(G) ¹¹,—CO—NR_(G) ¹¹R_(G) ¹¹* or —CO-R_(G) ¹ for R_(A) ¹⁸ and R_(A) ¹⁹independently of one another is understood as meaning, for example, theradicals described above for R_(G) ¹², preferably hydrogen or a branchedor unbranched, optionally substituted C₁-C₈-alkyl radical.

Z¹, Z², Z³, Z⁴ are independently of one another nitrogen, C—H,C-halogen, such as C—F, C—Cl, C—Br or C—I or a branched or unbranched,optionally substituted C—C₁-C₄-alkyl radical which is composed of acarbon radical and, for example, a C₁-C₄-alkyl radical described abovefor R_(A) ⁶ or a branched or unbranched optionally substitutedC—C₁-C₄-alkoxy radical which is composed of a carbon radical and, forexample, a C₄-alkoxy radical described above for R_(A) ⁷.

Z⁵ is oxygen, sulfur or a radical NR_(A) ⁸.

Preferred structural elements A are composed of at least one preferredradical of the radicals belonging to the structural element A, while theremaining radicals are widely variable.

Particularly preferred structural elements A are composed of thepreferred radicals of the structural element A.

In a preferred embodiment, the spacer structural element E is understoodas meaning a structural element that consists of a branched orunbranched aliphatic C₂-C₃0-hydrocarbon radical which is optionallysubstituted and contains heteroatoms and/or of a 4-to 20-memberedaliphatic or aromatic mono- or polycyclic hydrocarbon radical which isoptionally substituted and contains heteroatoms.

In a further preferred embodiment, the spacer structural element E iscomposed of two to four substructural elements, selected from the groupconsisting of E¹ and E², where the sequence of linkage of thesubstructural elements is arbitrary and E¹ and E² have the followingmeanings:

-   -   E¹ is a substructural element of the formula I_(E1)

—(Y_(E))_(k1)—(CR_(E) ¹R_(E) ²)_(c)-(Q_(E))_(k2)-(-CR_(E) ³R_(E)⁴)_(d)-I_(E1)

and

-   -   E² is a substructural element of the formula I_(E2)

—(NR_(E) ¹¹)_(k3)—(CR_(E) ⁵R_(E) ⁶)_(f)-(Z_(E))_(k4)-(CR_(E) ⁷R_(E)⁸)_(g)-(X_(E))_(k)S—(CR_(E) ⁹R_(E) ¹⁰)_(h)-(NR_(E) ¹¹)_(k)6-I_(E)2,

wherec, d, f, g, h

-   -   independently of one another are 0, 1 or 2,        k1, k2, k3, k4, k5, k6    -   independently of one another are 0 or 1,

XE, QE

-   -   independently of one another are an optionally substituted 4- to        11-membered mono- or polycyclic, aliphatic or aromatic        hydrocarbon which can contain up to 6 double bonds and up to 6        identical or different heteroatoms selected from the group N, O        and S, where the ring carbons and/or the ring nitrogens can        optionally be substituted,

YE, ZE

-   -   independently of one another are CO, CO—NR_(E) ¹², NR_(E) ¹³-CO,        sulfur, SO, SO₂, SO₂—NR_(E) ¹², NR_(E) ¹²—SO₂, CS, CS—NR_(E) ¹²,        NR_(E) ¹²—CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene, CR_(E)        ¹³-O—CR.sub- .E¹⁴, C(═CR_(E) ¹³R_(E) ¹⁴), CR_(E) ¹³═CR_(E)-¹⁴,        —CR_(E) ¹³(CR_(E) ¹⁵)—CHR_(E) ¹⁴- or —CHR_(E) ¹³-CR_(E)        ¹⁴(0R_(E) ¹⁵)-,    -   R_(E) ¹, R_(E) ², R_(E) ³, R_(E) ⁴, R_(E) ⁵, R_(E) ⁶, R_(E) ⁷,        R_(E) ⁸, R_(E) ⁹, R_(E) ¹⁰    -   independently of one another are hydrogen, halogen, a hydroxyl        group, a branched or unbranched, optionally substituted        C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl or alkylenecycloalkyl        radical, a radical —(CH₂)_(x)—(W_(E)).su- b.z- R_(E) ¹⁷, an        optionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl,        hetaryl or hetarylalkyl radical or independently of one another        in each case two radicals R_(E) ¹ and R_(E) ² or R_(E) ³ and        R_(e) ⁴ or R_(E) ⁵ and R_(E) ⁶ or R_(E) ⁷ and R_(E) ⁸ or R_(E) ⁹        and R_(E) ¹⁰ together are, a 3- to 7-membered, optionally        substituted, saturated or unsaturated carbocycle or heterocycle        which can contain up to three heteroatoms selected from the        group O, N and S,    -   x is 0, 1, 2, 3 or 4,    -   z is 0 or 1,    -   W_(E) is —CO—, —CO—N(R_(W) ²)—, —N(R_(W) ²)—Co—, —N(R_(W)        ²)—CO—N(R_(W) ²*)—, —N(R_(W) ²)—CO—O—, —O—, —S—, —SO₂—,        —SO₂—N(R_(W) ²)—, —SO₂—O—, —CO—O—, —O—CO—, —O—CO—N(R_(W) ²)—,        —N(R_(W) ²)— or —N(R_(W) ²)—SO₂—,    -   R_(W) ², R_(W) ²*    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₈-alkynyl, CO—C₁-C₆-alk- yl, CO—O—C₁-C₆-alkyl or        SO₂—C₁-C₆-alkyl radical or an optionally substituted hetaryl,        hetarylalkyl, arylalkyl, C₃-C₇-cycloalkyl, CO—O-alkylenearyl,        CO-alkylenearyl, CO-aryl, SO₂-aryl, CO-hetaryl or        SO₂-alkylenearyl radical,    -   R_(E) ¹⁷ is hydrogen, a hydroxyl group, CN, halogen, a branched        or unbranched, optionally substituted C₁-C₆-alkyl radical, an        optionally substituted C₃-C₇-cycloalkyl, aryl, hetaryl or        arylalkyl radical, a C₂-C₆-alkynyl or C₂-C₆-alkenyl radical        optionally substituted by C₁-C₄alkyl or aryl, an optionally        substituted C₆-C₁2-bicycloalkyl,        C₁-C₆-alkylene-C₆-C₁2—bicycloalkyl, C₇-C₂0-tricycloalkyl or        C₁-C₆-alkylene-C- ₇-C₂0-tricycloalkyl radical, or a 3- to        8-membered, saturated or ausatutated heterocycle substituted by        up to three identical or different radicals, which can contain        up to three different or identical heteroatoms O, N, S, where        two radicals together can be a fused, saturated, unsaturated or        aromatic carbocycle or heterocycle which can contain up to three        different or identical heteroatoms O, N, S and the cycle can        optionally be substituted or a further, optionally substituted,        saturated, unsaturated or aromatic cycle can be fused to this        cycle, or the radical R_(E) ¹⁷ forms, together with R_(W) ² or        R_(W) ²* a saturated or unsaturated C₃-C₇-heterocycle which can        optionally contain up to two further heteroatoms selected from        the group O, S and N,    -   R_(E) ¹¹, R_(E) ¹¹*    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl,        C₁-C₆-alkoxyalkyl, C₂-C₆-alkenyl, C₂-C₁2-alkynyl,        CO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, CO—NH—C₁-C₆-alkoxyalkyl,        CO—NH—C₁-C₆-alkyl or SO₂—C₁-C₆-alkyl radical or an optionally        substituted hetaryl, arylalkyl, C₃-C₇-cycloalkyl,        CO—O-alkylenearyl, CO—NH-alkylenearyl, CO-alkylenearyl, CO-aryl,        CO—NH-aryl, SO₂-aryl, CO-hetaryl, SO₂-alkylenearyl, SO₂-hetaryl        or SO₂-alkylenehetaryl radical,    -   R_(E) ¹² is hydrogen, a branched or unbranched, optionally        substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₈-alkynyl radical,        an optionally substituted C₃-C₇-cycloalkyl, hetaryl, arylalkyl        or hetarylalkyl radical or a radical CO—R_(E) ¹⁶, COOR_(E) ¹⁶ or        SO₂—R_(E) ¹⁶,    -   R_(E) ¹³, R_(E) ¹⁴    -   independently of one another are hydrogen, a hydroxyl group, a        branched or unbranched, optionally substituted C₁-C₆-alkyl,        C₁-C₄-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl or alkylenecycloalkyl        radical or an optionally substituted C₃-C₇-cycloalkyl, aryl,        arylalkyl, hetaryl or hetarylalkyl radical,    -   R_(E) ¹⁵ is hydrogen, a branched or unbranched, optionally        substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl or        alkylenecycloalkyl radical or an optionally substituted        C₃-C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl        radical,    -   R_(E) ¹⁶ is hydrogen, a hydroxyl group, a branched or        unbranched, optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₆-alkynyl or C₁-C₅-alkylene-C₁-C₄-alkoxy radical, or an        optionally substituted aryl, heterocycloalkyl,        heterocycloalkenyl, hetaryl, C₃-C₇-cycloalkyl,        C₁-C₄-alkylene-C₃-C₇-cycl- oalkyl, arylalkyl,        C₁-C₄-alkylene-C₃-C₇-heterocycloalk- yl        C₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl or hetarylalkyl radical.

The coefficient c is preferably 0 or 1, the coefficient d is preferably1 or 2, the coefficients f, g, h independently of one another arepreferably 0 or 1 and K⁶ is preferably 0.

An optionally substituted 4- to 11-membered mono- or polycyclicaliphatic or aromatic hydrocarbon which can contain up to 6 double bondsand up to 6 identical or different heteroatoms selected from the groupconsisting of N, O, S, where the ring carbons or ring nitrogens canoptionally be substituted, for Q_(E) and X_(E) independently of oneanother is preferably understood as meaning optionally substitutedarylene, such as optionally substituted phenylene or naphthylene oroptionally substituted hetarylene such as the radicals

and their substituted or fused derivatives, or radicals of the formulaeI_(E) ¹ to I_(E) ¹¹,

-   -   where the incorporation of the radicals can take place in both        orientations. Aliphatic hydrocarbons are understood as meaning,        for example, saturated and unsaturated hydrocarbons.    -   Z⁶ and Z⁷ are independently of one another CH or nitrogen.    -   Z⁸ is oxygen, sulfur or NH,    -   Z⁹ is oxygen, sulfur or NR_(E) ²⁰.    -   r1, r2, r3 and t are independently of one another 0, 1, 2 or 3.    -   s and u are independently of one another 0, 1 or 2.

Particularly preferably, XE and QE independently of one another areoptionally substituted phenylene, a radical

-   -   and their substituted or fused derivatives, or radicals of the        formulae IE¹, IE², IE³, IE⁴ and IE⁷, where the incorporation of        the radicals can take place in both orientations.    -   RE¹⁸ and RE¹⁹ are independently of one another hydrogen, —NO₂,        —NH₂, —CN, —COOH, a hydroxyl group, halogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl, C₁-C₄-alkoxy,        C₂-C₆-alkenyl, C₂-C₆-alkynyl or alkylenecycloalkyl radical or an        optionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl,        hetaryl or hetarylalkyl radical, as in each ease described        above.

RE²⁰ is, independently of one another, hydrogen, a branched orunbranched, optionally substituted C₁-C₆-alkyl, C₁-C₆-alkoxyalkyl,C₃-C₁₂-alkynyl, CO—C₁-C₆-alkyl, C0-O—C₁-C₆-alkyl or SO₂—C₁-C₆-alkylradical or an optionally substituted C₃-C₇-cycloalkyl, aryl, arylalkylCO—O-alkylenearyl, CO-alkylenearyl, CO-aryl, SO₂-aryl, hetaryl,CO-hetaryl or SO₂alkylenearyl radical, preferably hydrogen or a branchedor unbranched, optionally substituted C₁-C₆-alkyl radical.

-   -   YE and ZE are independently of one another CO, CO—NRE¹²,        NRE¹²-CO, sulfur, SO, SO₂, SO₂—NRE¹², NRE¹²-SO₂, CS, CS—NRE¹²,        NRE¹²-CS, CS—O, O—CS, CO—O, O—CO, oxygen, ethynylene,        CRE¹³-O—CRE¹⁴, C(═CRE¹³RE¹⁴), CRE¹³═CRE¹⁴,        —CRE¹³(ORE¹⁵)—CHRE¹⁴—or —CHRE¹³-CRE¹⁴(ORE¹⁵)-, preferably CO,        SO₂ and oxygen.    -   RE¹² is hydrogen, a branched or unbranched, optionally        substituted C₁-C₆-alkyl, C₂-C₆-alkenyl or C₂-C₈-alkynyl radical        or an optionally substituted C₃-C₇-cycloalkyl, hetaryl,        arylalkyl or hetarylalkyl radical, such as correspondingly        described above for RG⁷ or a radical CO-RE¹⁶, COORE¹⁶ or        SO₂—RE¹⁶, preferably hydrogen, methyl, allyl propargyl and        cyclopropyl.

A branched or unbranched, optionally substituted C₁-C₆-alkyl,C₂-C₆-alkenyl or C₂-C₆-alkynyl radical or an optionally substitutedC₃-C₇-cycloalkyl, aryl, arylalkyl, hetaryl or hetarylalkyl radical forRE¹³, RE¹⁴ or RE¹⁵ independendy of one another is understood as meaning,for example, the corresponding radicals described above for RG⁷.

A branched or unbranched, optionally substituted C₁-C₄-alkoxy radicalfor RE¹³ or RE¹⁴ independently of one another is understood as meaning,for example, the C₁-C₄-alkoxy radicals described above for RA¹⁴.

Preferred alkylenecycloalkyl radicals for RE¹³ ₁ RE¹⁴ or RE¹⁵independently of one another are, for example, theC₁-C₄-alkylene-C₃-C₇-cycloalkyl radicals described above for RG⁷.

A branched or unbranched, optionally substituted C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl or C₁-C₅-alkylene-C₁-C₄-alkoxy radical, oran optionally substituted aryl, heterocycloalkyl, heterocycloalkenyl,hetaryl, C₃-C₇-cycloalkyl, C₁-C₄-alkylene-C₃-C.s-ub.7-cycloalkyl,arylalkyl, C₁-C₄-akylene-C₃-C₇-heter- ocycloalkyl,C₁-C₄-alkylene-C₃-C₇-heterocycloalkenyl hetarylalkyl radical for RE¹⁶ isunderstood as meaning, for example, the corresponding radicals describedabove for RG¹¹.

A branched or unbranched, optionally substituted C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl or alkylenecycloalkyl radical or anoptionally substituted C₃-C₇-cycloalkyl, aryl, arylalkyl, hetaryl orhetarylalkyl radical for RE¹, RE², RE³, RE⁴, RE⁵, RE⁶, RE⁷, RE⁸, RE⁹ orRE¹⁰ independently of one another is understood as meaning, for example,the corresponding radicals mentioned above for R_(G) ⁷.

Further, two radicals RE³ and RE⁴ or RE⁵ and RE⁶ or RE⁷ and RE⁸ or RE⁹and RE¹⁰ can in each ease independently of one another together form a3- to 7-membered, optionally substituted, saturated or unsaturatedcarbo- or heterocycle, which can contain up to three heteroatoms fromthe group consisting of O, N and S.

The radical —(CH2)x—(WE) Z-RE¹⁷ is composed of a CO—C₄-alkylene radical,optionally a bonding element WE selected from the group —CO—,—CO—N(R²)—, —N(R¹²)—CO—, —N(RW²)—CO—N(RW²*)-, —N(R²)—CO—O—, —O—, —S—,—SO₂—, —SO₂—N(RW²)—, —SO₂—O—, —CO—O—, —O—CO—O—CO—N(RW²)—, —N(RW²)— or—N(RW²)—SO₂—, preferably selected from the group —CO—N(RW²)—,—N(RW²)—CO—, —O—, —SO₂—N(RW²)—, —N(RW²)— or —N(RW²)—SO₂, and the radicalRE¹⁷, where

-   -   RW² and RW²*    -   independently of one another are hydrogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,        C₂-C₈-alkynyl, CO—C₁-C₆-alk- yl, CO—O—C₁-C₆-alkyl or        SO₂—C₁-C₆-alkyl radical or an optionally substituted hetaryl,        hetarylalkyl, arylalkyl, C₃-C-₇-cycloalkyl, CO—O-alkylenearyl,        CO-alkylenearyl, CO-aryl, SO₂-aryl, CO-hetaryl or        SO₂-alkylenearyl radical, preferably independently of one        another are hydrogen, methyl, cyclopropyl, ally, propargyl, and    -   RE¹⁷    -   is hydrogen, a hydroxyl group, CN, halogen, a branched or        unbranched, optionally substituted C₁-C₆-alkyl radical, an        optionally substituted C₃-C₇-cycloalkyl, aryl, hetaryl or        arylalkyl radical, a C₂C₆alkynyl or C₂-C₆-alkenyl radical        optionally substituted by C₁-C₄alkyl or aryl, an optionally        substituted C₆-C₁₂-bicycloalkyl,        C₁-C₆-alkylene-C₆-C₁₂-bicycloalkyl, C₇-C₂₀-tricycloalkyl or        C₁-C₆-alkylene-C₇-C- 20-tricycloalkyl radical, or a 3- to        8-membered, saturated or unsaturated heterocycle which is        substituted by up to three identical or different radicals and        can contain up to three different or identical heteroatoms O, N,        S, where two radicals together can be a fused, saturated,        unsaturated or aromatic carbocycle or heterocycle which can        contain up to three different or identical heteroatoms O, N, S,        and the cycle can be optionally substituted or a further,        optionally substituted, saturated, unsaturated or aromatic cycle        can be fused to this cycle, such as optionally substituted        2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-pyrrolyl,        3-pyrrolyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl,        5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-pyrimidyl,        4-pyrimidyl, 5-pyrimidyl, 6-pyrimidyl, 3-pyrazolyl, 4-pyrazolyl,        5-pyrazolyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl,        2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyridazinyl,        4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl,        2-(1,3,4-thiadiazolyl), 2-(1,3,4)-oxadiazolyl, 3-isoxazolyl,        4-isoxazolyl, 5-isoxazolyl or triazinyl.

Further, RE¹⁷ and RW² or RW²* can together form a saturated orunsaturated C₃-C₇-heterocycle which can optionally contain up to twofurther heteroatoms selected from the group consisting of O, S and N.

Preferably, the radicals RE¹⁷ and RW² or RW²* together form a cyclicamine as the C₃-C₇-heterocycle in the case where the radicals are bondedto the same nitrogen atom, such as N-pyrrolidinyl, N-hexahydroazepinyl,N-morpholinyl or N-piperazinyl where in heterocycles which carry freeamine protons, such as N-piperazinyl, the free amine protons can bereplaced by customary amine protective groups, such as methyl, benzyl,Boc (tert-butoxycarbonyl), Z (benzyloxycarbonyl), tosyl,—SO₂—C₁-C₄-alkyl, —SO₂-phenyl or —SO₂-benzyl.

Preferred radicals for RE¹, RE², RE³, RE⁴, RE⁵, RE⁶, RE⁷, RE⁸, RE⁹ orRE¹⁰ are independently of one another hydrogen, halogen, a branched orunbranched, optionally substituted C₁-C₆-alkyl radical, optionallysubstituted aryl or the radical —(CH₂)x—(WE)z—RE¹⁷.

Particularly preferred radicals for RE¹, RE², RE³, RE⁴, RE⁵, RE⁶, RE⁷,RE⁸, RE⁹ or RE¹⁰ are independently of one another hydrogen, F, abranched or unbranched, optionally substituted C₁-C₄-alkyl radical, inparticular methyl.

A branched or unbranched, optionally substituted C₁-C₆-alkoxyalkyl,C₂-C₆-alkenyl, C₂-C₁₂-alkynyl or arylalkyl radical or an optionallysubstituted aryl, hetaryl or C₃-C₇-cycloalkyl for RE¹¹ and RE¹¹* instructural element E independently of one another is understood asmeaning, for example, the corresponding radicals described above forRG⁷.

The branched or unbranched, optionally substituted radicalsCO—C₁-C₆-alkyl, CO—O—C₁-C₆-alkyl, CO—NH—C₁-C₆-alkoxalkyl,CO—NH—C₁-C₆-alkyl or SO₂—C₁-C₆-alkyl radical or the optionallysubstituted radicals Co-O-alkylenearyl, CO—NH-alkylenearyl,CO-alkylenearyl, CO-aryl, CO—NH-aryl, SO₂-aryl, CO-hetaryl,SO₂-alkylenearyl, SO₂-hetaryl or SO₂-alkylenehetaryl for RE¹¹ and RE¹¹*independently of one another are composed, for example, of thecorresponding groups CO, COO, CONH or SO₂ and the corresponding radicalsmentioned above.

Preferred radicals for RE¹¹ or RE¹¹* are independently of one anotherhydrogen, a branched or unbranched, optionally substituted C₁-C₆-alkyk,C₁-C₆-alkoxy, C₂-C₆-alkenyl,

-   -   C₂-C₁₂-alkynyl or arylalkyl radical, or an optionally        substituted hetaryl or C₃-C₇-cycloalkyl radical.

Particularly preferred radicals for RE¹¹ or RE¹¹* are hydrogen, methyl,cyclopropyl, allyl or propargyl.

In a particularly preferred embodiment of structural element E₁,structural element E₁ is a radical —CH₂—CH₂—CO—, —CH₂—CH₂—CH₂—CO— or aC₁-C₅-alkylene radical.

In a particularly preferred embodiment of structural element E, thespacer structural element E used is a structural element of the formulaI_(E1E2)

-E₂-E₁-  I_(E1E2)

-   -   where the structural elements E₂ and E₁ have the meanings        described above.

Preferred structural elements E are composed of at least one preferredradical of the radicals belonging to structural element E, while theremaining radicals are widely variable.

Particularly preferred structural elements E are composed of thepreferred radicals of structural element E.

Preferred structural elements B are composed either of the preferredstructural element A, while E is widely variable or of the preferredstructural element E, while A is widely variable.

The compounds of the formula I, and also the intermediates for theirpreparation, can have one or more asymmetric substituted carbon atoms.The compounds can be present as pure enantiomers or pure diastereomersor as a mixture thereof. The use of an enantiomerically pure compound asthe active compound is preferred.

The compounds of the formula I can also be present in other tautomericforms.

The compounds of the formula I can also be present in the form ofphysiologically tolerable salts.

The compounds of the formula I can also be present as prodrugs in a formin which the compounds of the formula I are liberated underphysiological conditions. By way of exammple, reference may be made hereto the group T in structural element L, which in some cases containsgroups which are hydrolyzable to the free carboxylic acid group underphysiological conditions. Derivatized structural elements B or A arealso suitable which liberate the structural element B or A respectivelyunder physiological conditions.

In preferred compounds of the formula I, in each case one of the threestructural elements B, G or L has the preferred range, while theremaining structural elements are widely variable.

In particularly preferred, compounds of the formula I, in each case twoof the three structural elements B, G or L have the preferred range,while the remaining structural elements are widely variable.

In very particularly preferred compounds of the formula I, in each caseall three structural elements B, G or L have the preferred range, whilethe remaining structural element is widely variable.

Preferred compounds of the formula I contain, for example, the preferredstructural element G, while the structural elements B and L are widelyvariable.

In particularly preferred compounds of the formula I, for example, B isreplaced by the structural element A-E- and the compounds contain, forexample, the preferred structural element G and the preferred structuralelement A, while the structural elements E and L are widely variable.

Further particularly preferred compounds of the formula I contain, forexample, the preferred structural element G and the preferred structuralelement A, while the structural elements E and L are widely variable.

Very particularly preferred compounds of the formula I in which A-E- isB- are listed below, the number before the text block being the numberof an individualized compound of the formula I, and in the text blockA-E-G-L the abbreviations being separated by a bonding dash in each casefor an individual structural element A, E, G or L and the meaning of theabbreviations of the structural elements being explained after thetable.

-   -   No. A-E-G-L    -   1 bhs-dibema2-mmophec-es    -   2 gua-mepipe2-phec-es    -   3 gua-35thima2-4phaz-es    -   4 bhs-apma2-pclphec-es gua-a23thima2-4bec-es    -   6 bim-dibema2-4bec-es    -   7 2py-bam2-pipmaz-es    -   8 bim-bam2-mmphec-es    -   9 2py-a23thima2-thec-es gua-pipa2-4pec-es    -   11 dhim-35thima2-thec-es    -   12 gua-a24thima2-amaz-es    -   13 bim-pyma2-phec-es    -   14 gua-a24thima2-3bzlaz-es bhs-inda2-thec-es    -   16 2py-a24thima2-3bec-nes    -   17 gua-a24thima2-phaz-es    -   18 gua-bam2-pymaz-es    -   19 gua-me35thima2-phec-es    -   2py-dibema2-4pec-es    -   21 bhs-35thima2-thec-gs    -   22 bhs-aaf-3bec-es    -   23 im-35thima2-thec-es    -   24 bhs-a23thima2-3ipec-es bim-pipa2-4pec-es    -   26 bhs-mea2-thec-es    -   27 gua-dibema2-7 cmc-es    -   28 2py-apma2-phaz-es    -   29 bhs-apma2-7 cmc-es thpym-bam2-4pec-es    -   31 bim-me35thima2-4pec-es    -   32 bim-a24thima2-3bec-es    -   33 bhs-me42thiaz2-phaz-es    -   34 2py-42thiaz2-thec-es    -   2py-pipa2-cpec-es    -   36 bim-35thima2-pymaz-es    -   37 bhs-a23thima2-3bec-es    -   38 2py-apma2-ppec-es    -   39 bhs-35thima2-pclphec-es    -   40 2py-buta-3bec-es    -   41 bim-a23thima2-7 cmc-gs    -   42 bhs-hexa-thec-es    -   43 bim-a23thima2-4pec-f2es    -   44 2py-35thima2-7 cmc-es    -   45 gua-chex2-4pec-es    -   46 bhs-edia2-thec-es    -   45 47 bhs-bam2-phaz-es    -   48 amim-35thima2-3bec-es    -   49 clim-apma2-3bec-es    -   50 gua-pipa2-phec-mals    -   51 am2py-a24thima2-thec-es    -   52 bhs-apma2-phaz-gs    -   53 2py-inda2-thec-es    -   54 bim-35thima2-mmophec-es    -   55 2py-inda2-3bec-es    -   56 2py-mepipe2-thec-es    -   57 bim-bam2-thec-es    -   58 bim-bam2-4phaz-es    -   59 2py-apma2-3bec-es    -   60 bhs-a24thima2-pmophec-es    -   61 bim-dibema2-thec-es    -   62 mam2py-a24thima2-phaz-es    -   63 2py-mea2-3bec-es    -   64 bim-penta-4pec-es    -   65 gua-prodia2-7 cmc-es    -   66 bhs-dibema2-cpec-es    -   67 2py-hexa-phaz-es    -   68 gua-apma2-3ipec-es    -   69 bim-apma2--phec-ms    -   70 gua-35thima2-phec-ps    -   71 bim-pipa2-3bec-es    -   72 gua-a23thima2-phec-es    -   73 2py-42thiaz2-phaz-es    -   74 bim-me35thima2-7 cmc-es    -   75 bhs-bam2-mpphec-es    -   76 gua-dibema2-thec-es    -   77 clim-bam2-thec-es    -   78 dimethpym-a23thima2-thec-es    -   79 gua-dibema2-4pec-cs    -   80 bhs-apma2-3bzlaz-es    -   81 gua-a24thima2-4pec-es    -   82 bhs-pyma2-phaz-es    -   83 gua-apma2-7 cmc-es    -   84 bhs-a23thima2-4phaz-es    -   85 bhs-penta-3bec-es    -   86 gua-aof-7 cmc-es    -   87 2py-a23thima2-phaz-ms    -   88 bim-dibema2-phaz-es    -   40 89 bim-35thima2-phec-as    -   90 bim-apma2-cpec-es    -   91 bhs-pipa2-3bec-nes    -   92 2py-pipa2-mmophec-es    -   93 bhs-35thima2-3bec-es    -   45 94 bhs-dibema2-phaz-es    -   95 gua-pipa2-3bec-es    -   96 bim-pipa2-phec-es    -   97 gua-42thiaz2-phec-es    -   98 pippy-a24thima2-4pec-es    -   99 2py-35thima2-thec-es    -   100 2py-bam2-7 cmc-es    -   101 2py-35thima2-pmophec-es    -   102 bhs-dibema2-thec-es    -   103 bim-aof-4pec-es    -   104 bim-hexa-phec-es    -   105 2py-a24thima2-7 cmc-es    -   106 gua-a24thima2-phec-gs    -   107 gua-me25thima2-7 cmc-es    -   108clim-a24thima2-7 cmc-es    -   109 gua-apma2-4pec-es    -   110 bim-35thima2-cpec-es    -   111 2py-me35thima2-thec-es    -   112 bhs-a24thima2-dbc-es    -   113 bim-bam2-4pec-es    -   114 amim-a24thima2-4pec-es    -   115 2py-dibema2-amec-es    -   116 2py-a23thima2-dbc-es    -   117 bim-bam2-4pec-ps    -   118 2py-ba m2-mmophec-es    -   119 bim-apma2-3bec-es    -   120 bhs-pdagk-thec-es    -   121 gua-42thiaz2-7 cmc-es    -   122 gua-a23thima2-thec-es    -   123 bim-apma2-4pec-es    -   124 thpym--35thima2-phec-es    -   125 bim-bam2-7 cmc-es    -   126 mam2py-bam2-4pec-es    -   127 bhs-edia2-3bec-es    -   128 bhs-a23thima2-amec-es    -   129 gua-dibema2-3bec-es    -   130 bim-me42thiaz2-7 cmc-es    -   131 bhs-a23thima2-phec-es    -   132 bim-diberma2-mpphec-es    -   133 2py-prodia2-thec-es    -   134 bhs-bam2-mophaz-es    -   135 bhs-a24thima2-7 cmc-es    -   40 136 im-dibema2-4pec-es    -   137 imhs-a24thima2-thec-es    -   138 bhs-a24thima2-dmaphec-es    -   139 2py-pipa2-dmaphec-es    -   140 2py-a24thima2-4pec-es    -   141 2py-dibema2-7 cmc-es    -   142 bhs-apma2-phaz-es    -   143 gua-pipa2-mophaz-es    -   144 dhim-dibema2-4pec-es    -   145 gua-pipa2-mpphec-es    -   146 bim-a23thima2-4pec-es    -   147 2py-dibema2-4phaz-es    -   148 bim-42thiaz2-4pec-es    -   149 am2py-dibema2-3bec-es    -   150 bim-pipa2-7 cmc-es    -   151 gua-bam2-dmaphec-es    -   152 bhs-pipa2-amec-es    -   153 2py-apma2-mpphec-es    -   154 2py-hexa-3bec-es    -   155 bim-apma2-7 cmc-es    -   156 bim-a23thima2-pclphec-es    -   157 gua-a24thima2-pclphec-es    -   158 bim-a23thima2-phec-es    -   159 bim-a24thima2-4pec-es    -   160 bhs-a23thima2-7 cmc-es    -   161 dimethpym-dibema2-phaz-es    -   162 2py-me25thima2-3bec-es    -   163 bhs-aof-thec-es    -   164 gua-dibema2-phec-f2es    -   165 amim-a23thima2-phec-es    -   166 2py-bam2-pclphec-es    -   167 bhs-pyma2-thec-es    -   168 2py-a24thima2-3bec-es    -   169 bim-bam2-phec-es    -   170 bim-35thima2-7 cmc-es    -   171 bhs-35thima2-pipmaz-es    -   172 bim-prodia2-phec-es    -   173 bim-35thima2-phec-es    -   174 gua-edia3-4pec-es    -   175 gua-a23thima2-ppec-es    -   176 gua-pipeme2-phec-es    -   177 gua-dibema2-phaz-es    -   178 2py-bam2-3bec-es    -   179 bhs-bam2-3bec-mals    -   180 mam2py-apma2-7 cmc-es    -   181 bhs-bam2-pmophec-es    -   182 gua-bam2-7 cmc-es    -   183 gua-buta-phec-es    -   184 bim-pyma2-7 cmc-es    -   185 2py-pipa2-thec-ms    -   186 bhs-dibema2-dmaphec-es    -   187 bim-a24thima2-ppec-es    -   188 am2py-bam2-7 cmc-es    -   189 bim-buta-7cmc-es    -   190 im pipa2-phec-es    -   191 gua-dibema2-4pec-gs    -   192 2py-buta-thec-es    -   193 2py-pipa2-7 cmc-es    -   194 2py-apma2-phec-es    -   195 bim-pipa2-phec-gs    -   196 bim-me25thima2-phec-es    -   191 2py-pyma2-3bec-es    -   198 gua-bam2-pmophec-es    -   199 gua-35thima2-4pec-es    -   200 2py-pipeme2-thec-es    -   201 bhs-35thima2-phaz-f2es    -   202 bhs-edia3-phaz-es    -   203 2py-apma2-thec-pms    -   204 im apma2-phaz-es    -   205 bim-chex2-phec-es    -   206 bhs-35thima2-4pec-es    -   207 gua-a23thima2-phaz-es    -   208 2py-me25thima2-phaz-es    -   209 2py-a23thima2-pmophec-es    -   210 bhs-chex2-3bec-es    -   211 2py-dibema2-3ipec-es    -   212 2py-bam2-phec-es    -   213 bhs-dibema2-phec-es    -   214 bim-a24thima2-thec-es    -   215 bim-pipa2-thec-es    -   216 bhs-buta-phaz-es    -   217 bhs-mepipe2-phaz-es    -   218 gua-buta-4pec-es    -   219 am2py-a23thima2-phaz-es    -   220 gua-bam2-thec-es    -   221 gua-pdagk-4pec-es    -   222 bim-pdagk-phec-es    -   223 2py-35thima2-phec-es    -   224 gua-35thima2-7 cmc-es    -   225 gua-bam2-3bec-es    -   226 bhs-bam2-3bec-es    -   227 gua-a23thima2-7 cmc-es    -   228 bhs-aepi2-thec-es    -   229 clim-pipa2-7 cmc-es    -   230 2py-a23thima2-3bec-es    -   231 bim-a23thima2-3bzlaz-es    -   232 bhs-pipa2-3bec-es    -   233 bim-pipa2-mmphec-es    -   234 clim-dibema2-phec-es    -   235 bhs-aepi2-3bec-es    -   236 2py-apma2-4pec-es    -   237 dhim-a23thima2-7 cmc-es    -   238 bim-pipa2-pclphec-es    -   239 gua-mepipe2-7 cmc-es    -   240 gua-35thima2-3ipec-es    -   241 bhs-chex2-thec-es    -   242 bim-inda2-7 cmc-es    -   243 bhs-pipa2-phaz-es    -   244 imhs-pipa2-thec-es    -   245gua-apma2-4phaz-es    -   246 gua-me25thima2-4pec-es    -   247 gua-35thima2-phec-es    -   248 bim-pipa2-amaz-es    -   249 2py-a24thima2-4phaz-es    -   250 2py-me42thiaz2-3bec-es    -   251 imhs-apma2-phec-es    -   252 bhs-pipeme2-thec-es    -   253 dhim-a24thima2-phec-es    -   254 2py-a23thima2-7 cmc-es    -   255 2py-pipa2-pymaz-es    -   256 2py-me35thima2-3bec-es    -   257 bim-apma2-7 cmc-as    -   258 bhs-35thima2-amaz-es    -   259 mam2py-dibema2-thec-es    -   260 dimethpym-apma2-4pec-es    -   261 bhs-bam2-4bec-es    -   262 2py-a23thima2-cpec-es    -   263 mam2_(py-)35thima2-phec-es    -   264 am2py-apma2-phec-es    -   265 gua-a23thima2-4pec-es    -   266 bim-a24thima2-phec-es    -   267 2py-pipa2-thec-es    -   268 2py-dibema2-thec-es    -   269 pippy-pipa2-4pec-es    -   270 bim-dibema2-7 cmc-es    -   271 bim-dibema2-phec-es    -   272 gua-pdagk-7 cmc-es    -   273 bhs-35thima2-thec-es    -   274 bhs-a23thima2-mmphec-es    -   275 bhs-a23thima2-thec-nes    -   276 bim-me25thima2-7 cmc-es    -   277 2py-a24thima2-phec-es    -   278 gua-barn2-dbc-es    -   279 amim-dibema2-7 cmc-es    -   280 2py-a23thima2-4pec-es    -   281 thpym-dibema2-thec-es    -   282 2py-pipa2-phec-es    -   283 bhs-a24thima2-pymaz-es    -   284 gua-dibema2-amaz-es    -   285 dhim-bam2-3bec-es    -   286 gua-bam2-7 cmc-ms    -   287 bhs-edia3-thec-es    -   288 bim-a24thima2-phec-mals    -   289 bim-a24thima2-mophaz-es    -   290 gua-dibema2-phec-es    -   291 bhs-pipa2-4pec-es    -   292 bhs-apma2-pipmaz-es    -   293 gua-dibema2-pipmaz-es    -   294 gua-aepi2-4pec-es    -   295 gua-pipa2-ppec-es    -   296 bim-mea2-7 cmc-es    -   297 gua-pipa2-pmophec-es    -   298 imhs-bam2-7 cmc-es    -   299 gua-a24thima2-7 cmc-f2es    -   300 thpym-a23thima2-3bec-es    -   301 bim-mepipe2-7 cmc-es    -   302 thpym-pipa2-phaz-es    -   303 bim-aaf-7 cmc-es    -   304 bim-edia3-phec-es    -   305 2py-a24thima2-thec-es    -   306 bim-pipa2-phaz-es    -   307 dimethpym-bam2-phec-es    -   308 bim-a24thima2-phaz-es    -   309 bhs-bam2-phaz-pms    -   310 2py-35thima2-3bec-es    -   311 2py-35thima2-mophaz-es    -   312 gua-apma2-phaz-es    -   313 bim-apma2-phaz-es    -   314 gua-35thima2-7 cmc-nes    -   315 bhs-pipa2-phec-es    -   316 bhs-mepipe2-3bec-es    -   317 gua-pipa2-phaz-es    -   318 2py-a23thima2-phec-es    -   319 2py-pipa2-4pec-es    -   320 gua-apma2-mmphec-es    -   321 2py-apma2-7 cmc-es    -   322 bhs-a24thima2-phec-es    -   323 bhs-a23thima2-4pec-es    -   324 bim-35thima2-phaz-es    -   325 bim-pipeme2-7 cmc-es    -   326 bhs-42thiaz2-3bec-es    -   327 pippy-a23thima2-phec-es    -   328 2py-aof-thec-es    -   329 2py-pdagk-phaz-es    -   330 gua-aepi2-7 cmc-es    -   331 dimethpym-pipa2-3bec-es    -   332 gua-35thima2-amec-es    -   333-bhs-inda2-phaz-es    -   334 2py-pipeme2-3bec-es    -   335 gua-apma2-4pec-nes    -   336 gua-edia2-4pec-es    -   337 gua-a24thima2-phec-es    -   338 gua-apma2-3bec-es    -   339 gua-aaf-phec-es    -   340 gua-apma2-thec-es    -   341 bim-apma2-pymaz-es    -   342 im a24thima2-phec-es    -   343 2py-a24thima2-ames-es    -   344 bim-pdagk-7 cmc-es    -   345 bim-pipa2-3bzlaz-es    -   346 2py-mea2-phaz-es    -   347 amim-bam2-phaz-es    -   348 2py-pipa2-3bec-es    -   349 dhim-apma2-phaz-es    -   350 2py-35thima2-4pec-es    -   351 bhs-aof-3bec-es    -   352 2py-dibema2-phaz-nes    -   353 gua-a24thima2-3bec-es    -   354 bhs-dibema2-pymaz-es    -   335 bim-a24thima2-4bec-es    -   356 bhs-bam2-4pec-es    -   357 bim-35thima2-thec-es gua-penta-phec-es    -   358 bim-buta-4pec-es    -   359 bhs-apma2-amaz-es    -   360 dimethpym-a24thima2-3bec-es    -   361 gua-a2-3thima2-7 cmc-mals    -   362 gua-dibema2-3bzlaz-es    -   363 2py-edia2-3bec-es    -   364 2py-aaf-thec-es    -   364 gua-a24thima2-7 cmc-es    -   365 2py-dibema2-mmphec-es    -   366 hs-apma2-3bec-es    -   357 im-dibema2-ppec-es    -   368 ua-35thima2-phaz-es    -   369 py-me42thiaz2-thec-es    -   370 im-35thima2-dbc-es    -   371 hs-prodia2-3bec-es    -   372 ua-35thima2-mmphec-es    -   373 hs-hexa-3bec-es    -   374 hs-penta-phaz-es    -   375 him-pipa2-phec-es    -   376 ua-bam2-phec-es    -   377 dhim-pipa2-phec-es    -   378 gua-bam2-phec-es    -   379 2py-apma2-phaz-mals    -   380 bim-apma2-dbc-es    -   381 gua-inda2-phec-es    -   382 2py-bam2thec-es    -   383 gua-pipa2-4bec-es    -   384 am2py-35thima2-4pec-es    -   383 bim-a24thima2-mpphec-es    -   386 2py-35thima2-4bec-es    -   387 bhs-pipa2-7 cmc-es    -   388 amim-pipa2-4pec-es    -   389 bhs-apma2-4pec-es    -   390 gua-a23thima2-phec-pms    -   391 bim-35thima2-4pec-es    -   392 bhs-a24thima2-thec-es    -   393 thpym-a24thima2-phaz-es    -   394 bim-mea2-phec-es    -   395 bim-a23thima2-thec-es    -   396 pippy-apma2-thec-es    -   397 2py-35thima2-ppec-es    -   398 im a23thima2-7 cmc-es    -   399 gua-mea2-4pec-es    -   400 gua-edia2-7 cmc-es    -   401 mam2py-pipa2-phaz-es    -   402 bhs-apma2-3bec-f2es    -   403 bim-aepi2-phec-es    -   404 2py-aepi2-phaz-es    -   405 2py-35thima2-thec-mals    -   406 2py-bam2-phaz-es    -   407 am2py-pipa2-thec-es    -   408 bhs-bam2-ppec-es    -   409 2py-dibema2-thec-ps    -   410 gua-pipa2-7 cmc-es    -   411 gua-bam2-4pec-as    -   412 bhs-apma2-thec-es    -   413 clim-35thima2-phaz-es    -   414 2py-bam2-amaz-es    -   415 bhs-pipa2-phaz-ps    -   416 gua-bam2-phaz-es    -   417 bhs-apma2-mmophec-es    -   418 gua-a24 thima2-thec-es    -   419 gua-chex2-7 cmc-es    -   420 2py-penta-thec-es    -   421 2py-edia2-phaz-es    -   422 gua-pipa2-phec-es    -   423 bim-chec2-4pec-es    -   424 gua-dibema2-mmophec-es    -   425 2py-35thima2-phaz-es    -   426 bim-dibema2-mophaz-es    -   427 bim-me42thiaz2-4pec-es    -   428 2py-pyma2-phaz-es    -   429 bhs-a24thima2-3bec-es    -   430 2py-penta-phaz-es    -   431 bim-dibema2-pmophec-es    -   432 gua-pipa2-4pec-pms    -   433 bim-a23thima2-mmophec-es    -   434 2py-dibema2-phec-es    -   435 gua-a24thima2-pipmaz-es    -   436 bim-apma2-phec-es    -   437 bhs-pipa2-mpphec-es    -   438 gua-a23thima2-3bec-es    -   439 bim-a23thima2-amaz-es    -   440 bhs-dibema2-4pec-es    -   441 imhs-35thima2-4pec-es    -   442 imhs-a23thima2-phaz-es    -   443 bim-bam2-phec-nes    -   444 bhs-dibema2-3bec-es    -   445 bhs-a24thima2-phaz-es    -   446 gua-apma2-7 cmc-ps    -   447 amim-apma2-thec-es    -   448 bim-edia3-7 cmc-es    -   449 gua-bam2-cpec-es    -   450 gua-inda2-4pec-es    -   451 gua-edia3-phec-es    -   452 2py-pipa2-dbc-es    -   453 2py-a24thima2-mmphec-es    -   454 bim-pipa2-pipmaz-es    -   455 2py-a23thima2-dmaphec-es    -   456 bim-a23thima2-3bec-es    -   457 2py-pdagk-3bec-es    -   458 bim-dibema2-3bec-es    -   459 bim-apma2-thec-es    -   460 2py-bam2-4pec-es    -   461 bhs-me35thima2-3bec-es    -   462 gua-35thima2-3bec-es    -   463 pippy-35thima2-3bec-es    -   464 2py-bam2-3bec-gs    -   465 2py-bam2-3bzlaz-es    -   466 bhs-pipeme2-phaz-es    -   467 bim-mepipe2-4pec-es    -   468 bhs-dibema2-thec-as    -   469 2py-apma2thec-es    -   470 bim-35thima2-3bec-es    -   471 bhs-mea2-phaz-es    -   472 bim-prodia2-4pec-es    -   473 bhs-mea2-phaz-es    -   474 gua-a24thima2-mmophec-es    -   475 gua-pipeme2-4pec-es    -   476 bim-a23thima2-phaz-es    -   477 gua-prodia2-phec-es    -   478 gua-dilbema2-pclphec-es    -   479 bhs-aaf-phaz-es    -   480 2py-chex2-phaz-es    -   481 bim-35thima2-dmaphec-es    -   482 imhs-dibema2-3bec-es    -   483 2py-bam2-thec-f2es    -   484 bhs-35thima2-phec-es    -   485 bim-a23thima2-7 cmc-es    -   486 bhs-apma2-phec-es    -   487 bim-apma2-pmophec-es    -   488 bim-dibema2-7 cmc-pms    -   489 gua-35thima2-thec-es    -   490 bhs-pipa2-4phaz-es    -   491 2py-dibema2-phaz-es    -   492 bim-apma2-dmaphec-es    -   493 bim-edia2-phec-es    -   494 2py-dibema2-3bec-es    -   495 bhs-35thima2-mmphec-es    -   496 gua-apma2-phec-es    -   497 bim-bam2-amec-es    -   498 gua-apma2-amec-cs    -   499 bhs-35thima2-7 cmc-es    -   500 bhs-me25thima2-thec-es    -   501 bhs-dibema2-7 cmc-es    -   502 gua-hexa-4pec-es    -   503 bim-bam2-3bec-es    -   504 bhs-pipa2-3ipec-es    -   505 2py-apma2-4bec-es    -   506 dimethpym-35thima2-7 cmc-es    -   507 bhs-bam2-phec-es    -   508 bhs-dibema2-3bec-ms    -   509 bhs-35thima2-3bzlaz-es    -   510 gua-penta-7 cmc-es    -   511 bhs-a23thima2-thec-es    -   512 clim-a23thima2-4pec-es    -   513 bhs-me42thiaz2-3bec-es    -   514 bhs-35thima2-phaz-es    -   515 bhs-a24thima2-4pec-es    -   516 bhs-a23thima2-phaz-es    -   517 bhs-bam2-thec-es    -   518 2py-35thima2-mpphec-es    -   519 bhs-dibema2-dbc-es    -   520 2py-35thima2-3bec-pms    -   521 2py-a24thima2-phaz-es    -   522 gua-aaf-7 cmc-es    -   523 gua-me42thiaz2-phec-es    -   524 bim-a23thima2-ipmaz-es    -   525 bim-a24thima2-7 cmc-es    -   526 im-bam2-3bec-es    -   527 bhs-a24thima2-cpec-es    -   528 bim-bam2-phaz-es    -   529 2py-apma2-mophaz-es    -   530 bim-pipa2-7 cmc-[2es    -   531 gua-a23thima2-mpphec-es    -   532 2py-a23thima2-3bec-as    -   533 gua-pyma2-4pec-es    -   534 2py-pipa2-phaz-es    -   535 2py-edia3-3bec-es    -   536 mam2py-a23thima2-3bec-es    -   537 2py-a24thima2-3ipec-es    -   538 2py-aof-phaz-es    -   539 gua-hexa-7 cmc-es    -   540 bhs-a23thima2-3bec-ps    -   541 bim-a24thima2-4pec-pms    -   542 bim-aaf-4pec-es    -   543 bhs-pipa2-thec-es    -   544 pippy-dibema2-7 cmc-es    -   545 gua-pipa2-thec-es    -   546 bhs-bam2-7 cmc-es    -   547 gua-bam2-4pec-es    -   548 bim-aepi2-4pec-es    -   549 2py-prodia2-phaz-es    -   550 2py-a23thima2-phaz-es    -   551 bim-35thima2-4pec-ms    -   552 bim-dibema2-4pec-mals    -   553 bhs-a24thima2-thec-ms    -   554 bim-42thiaz2-phec-es    -   555 2py-a24thima2-phaz-ps    -   556 bim-aof-phec-es    -   557 2py-a23thima2-pymaz-es    -   558 gua-a23thima2-mophaz-es    -   559 thpym-apma2-7 cmc-es    -   560 bim-bam2-3ipec-es    -   561 pippy-bam2-phaz-es    -   562im-dibema2-4pec-es

In the above list, the following abbreviations are used for thestructural units A, E, G and L.

A = Abbreviation

2py

dbim

bim

imhs

dimethpym

mam2py

am2py

thpym

bhs

gua

amim

clim

im

pippy

H = Abbreviation

edia2

pyma2

pipa2

aepi2

me35thima2

dibema2

edia3

buta

aaf

42thiaz2

chex2

bam2

apma2

pdagk

mepipe2

prodia2

inda2

35thima2

me25thima2

penta

aof

hexn

mea2

pipeme2

me42thiaz2

a23thima2

a24thima2

The bond from structural element G to structural unit L should beunderstood as meaning a double bond in the compound where L=as.

G = Abbreviation

4phaz

3bzlaz

mophaz

pipmaz

cpec

mpphec

amec

dbc

pclphec

thec

mmophec

3bec

phaz

pymaz

3ipec

phec

ppec

mmphec

amaz

4bec

dmaphec

4pec

pmophec

7eme

L = Abbreviation

es

gs

pms

f2es

mals

ps

ms

nes

as

The compounds of the formula I and the starting substances used fortheir preparation can generally be prepared by methods of organicchemistry known to the person skilled in the art, such as are describedin standard works such as Houben-Weyl (ed.). “Methoden der OrganischenChemie”[Methods of Organic Chemistry], Thieme-Verlag, Stuttgart, Taylor(ed.), “The Chemistry of Heterocyclic Compounds”, Wiley & Sons, NewYork, or March “Advanced Organic Chemistry”, 4^(th) Edition, Wiley &Sons. Further methods of preparing specific functional groups are alsodescribed in R. Larock, “Comprehensive Organic Transformations”,Weinheim 1989, in particular the preparation of alkenes, alkynes,halides, amines, ethers, alcohols, phenols, aldehydes, ketones,nitrites, carboxylic acids, esters, amides and acid chlorides.

Inhibitors of Integrin α_(v)β₆

The invention relates to novel integrin inhibitors of the formula I

in which

-   -   R¹, R^(1′) and R^(1″) are H, A, Ar, Het′, Hal, NO₂, CN, OR⁴,        COA, NHCOA, NH(CHO), NR⁴, COOR⁴ or CONHR⁴ ₂,    -   R2 is A, Ar, (CH₂)_(m)XA, (CH₂)_(m)OH, (CH₂)_(m)NH₂,        (CH₂)_(m)NHA, (CH₂)_(m)NA₂, (CH₂)_(m)NHCOA, (CH₂) NO₂, (CH₂)        COOR¹, (CH₂)_(m)CONH₂, (CH₂)_(m)X(CH₂)_(o)Ar,        (CH₂)_(m)X(CH₂)_(o)CHAr₂, (CH₂)_(m)X(CH₂)_(o)CAr₃,        (CH₂)_(m)XCOYA, (CH₂)_(m)XCOY(CH₂)_(o)Ar, (CH₂)_(m)X (CH₂)Het¹,        (CH₂)_(m)X (CH₂)CHHet¹ ₂, (CH₂)_(m)X(CH₂)_(o)CHet¹ ₃,        (CH₂)_(m)X(CH₂)_(o)YA, (CH₂)_(m)X (CH₂)_(o)NHCOA,        (CH₂)_(m)NHCONHR², (CH₂)_(m)CH₂A,| (CH₂)_(m)CHA₂, (CH₂)_(m)CA₃,        (CH₂)_(m)Ar, (CH₂)_(m)CHAr₂, (CH₂)_(m)CAr₃, (CH₂)_(m)Het¹,        (CH₂)_(m)CHHet¹ ₂, (CH₂)_(m)Chet¹ ₃, (CH₂)_(m)cycloalkyl,        (CH₂)_(m)-NH-C (═NH)-NH₂ or (CH₂)_(m)-(HN═) C-NH₂,    -   where X and Y, independently of one another, may be S, O, S═O,        SO₂ or NH, where, if R²=(CH₂)_(m)XSCOYA or (CH₂)_(m)XCOY        (CH₂)_(o)Ar, X and Y cannot be S═O or SO₂,    -   R^(2′) is H or A,    -   R² and R^(2′) together may alternatively be —(CH₂)_(p)—,0    -   R³ is H₂N—C (═NH)—, H₂N—C (═NH)—NH—, A—C (═NH)—NH—, Het²— or        Het²—NH—, where the primary amino groups may also be provided        with conventional amino-protecting groups,    -   R⁴ is H, A, Het¹, Hal, NO₂ or CN,    -   A is alkyl having from 1 to 8 carbon atoms,    -   Ar is phenyl, naphthyl, anthranyl or biphenyl, each of which is        unsubstituted or monosubstituted or polysubstituted by Hal, A,        OA, OH, CO—A CN, COOA, COOH, CONH₂, CONHA, CONA₂, CF₃, OCF₃ or        NO₂,    -   Het¹ is an aromatic monocyclic or bicyclic heterocyclic radical        having from 1 to 3 N, O and/or S atoms, with may be        unsubstitutod or monosubstituted or disubstituted by F, Cl, Br,        A, OA, SA, OCF3,—CO—A, CN, COOA, CONH₂, CONHA, CONA₂, NA₂ or        NO₂,    -   Het² is a monocyclic or bicyclic heterocyclic radical having        from 1 to 4 N atoms, which may be unsubstituted or mono        substituted or disubstituted by NH₂ or NHA,    -   m is 0, 1,2,3,4,5,6 or 8,    -   n is 1, 2,3,4,5 or 6,    -   o is 0, 1, 2 or 3,    -   p is 2, 3,4 or 5,        to their stereoisomers, and to their physiologically acceptable        salts and solvates.

The invention relates to novel peptides, of the formula I

R¹-Arg-X-Asp-Leu-Asp-Ser-Leu-Arg-R²  I

in which

-   -   R¹ denotes H, acetyl or acyl and    -   R² denotes —OH, OR³ NH₂,NHR³, N(R³)₂    -   R³ denotes alkyl, aralkyl, aryl, Het and    -   X denotes an amino acid of the formula II

in which

-   -   A denotes (CH₂)_(n)    -   R⁴ denotes H, alkyl, aralkyl or aryl, and    -   n denotes 1, 2, 3, 4, 5 or 6,    -   and the amino acid of the formula II is bonded to the adjacent        Arg via a peptide bond of the α-amino group and to the α-amino        group of the adjacent Asp via a peptide bond of the α-carboxyl        group.

The present invention also relates to the pharmaceutically usablepro-drugs, derivatives, solvates and stereoisomors of the compounds ofthe formula I and the salts thereof, including mixtures thereof in allratios.

The invention relates, in particular, to peptidic compounds selectedfrom the group of the formulae Ia)-I o)

-   -   I a) Ac-Arg-Dap(Psa)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I b) Ac-Arg-Dap(F5-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I c) Ac-Arg-Dap(2-NO₂-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I d) Ac-Arg-Dap(4-NO₂-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I e) Ac-Arg-Dap(2,4-NO₂-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I f) Ac-Arg-Dap(6-OMe-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I g) Ac-Arg-Dap(2-CF₃-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I h) Ae-Arg-Dap(3-CF3-PSA.)-Asp-Leu-Asp-Ser-Lt.-m-Arg-NH2,    -   I a) Ac-Arg-Dap(Me₅-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I j) Ac-Arg-Dap(4-tBu-PSA)-Asp-Leu-Asp-Ser-Leu-Arg-N H₂,    -   I k) Ac-Arg-Dap(BSA)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I l) Ac-Arg-Dap(iPrs)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I m) Ac-Arg-Dap(1-Nap)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I n) Ac-Arg-Dap(2-Nap)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   I o) Ac-Arg-Dap(4-Ph-Psa)-Asp-Leu-Asp-Ser-Leu-Arg-NH₂,    -   and pharmaceutically usable prodrugs, derivatives, solvates and        stereoisomers thereof, and salts thereof, including mixtures        thereof in all ratios, where the abbreviations used in brackets        in the formulae, I a)-I o) stand for the following radicals:

Psa phenylsulfonyl radical F5-PSA pentafluorophenylsulfonyl radical2-NO₂-PSA 2-nitrophenylsulfonyl radical 4-NO₂-PSA 4-nitrophenylsulfonylradical 2,4-NO₂-PSA 2,4-dinitrophenylsulfonyl radical 6-OMe-PSA6-methoxyphenylsulfonyl radical 2-CF₃-PSA2-trifluoromethylphenylsulfonyl radical 3-CF₃-PSA3-trifluoromethylphenylsulfonyl radical Me₅-PSApentamethylphenylsulfonyl radical 4-tBu-PSA 4-tert-butylphenylsulfonylradical Bsa benzylsulfonyl radical iPrs isopropylsulfonyl radical 1-Nap1-naphthylsulfonyl radical 2-Nap 2-naphthylsulfonyl radical 4-Ph-Psa4-phenylphenylsulfonyl radical

The abbreviations mentioned above and below for amino acid radicalsstand for the radicals of the following amino acids:

Asp or D aspartic acid Arg or R arginine Dap 2,3-diaminopropionic acidLeu or L leucine Ser or S serine Thr or T threonine

Furthermore, the following abbreviations above and below have thefollowing meanings:

Ac acetyl BOC tert-butoxycarbonyl BSA bovine serum albumin CBZ or Zbenzyloxycarbonyl DCCI dicyclohexylcarbodiimide DCM dichloromethane DIEAdiisopropylamine DMA N,N-dimethylacetamide DMF dimethylformamide EDCIN-ethyl-N,N′-(dimethylaminopropyl)carbodiimide Et ethyl FCAfluoresceincarboxylic acid FITC fluorescein isothiocyanate Fmoc9-fluorenylmethoxycarbonyl Fmoc-Dap(ivDde)N-α-Fmoc-N-γ-1-(4,4-dimethyl-2,6- dioxocyclohex-1-yli-dene)-3-methylbutyldiaminopropionic acid FTH fluoresceinthiourea HOBt1-hydroxybenzotriazole Me methyl MBHA 4-methylbenzhydrylamine Mtr4-methoxy-2,3,6-trimethylphenylsulfonyl NMP N-methylpyrrolidone HONSuN-hydroxysuccinimide OBut tent-butyl ester Oct octanoyl OMe methyl esterOEt ethyl ester Pbf 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonylPmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl POA phenoxyacetyl Salsalicyloyl TBS++ Tris buffered saline with divalent cations TBSA TBS +BSA TBTU 2-(1H-benzotriazol-1-yl)-1,1,3-tetramethyluroniumtetrafluoroborate TFA trifluoroacetic acid TIS triisopropylamine Trttrityl(triphenylmethyl).

If the above-mentioned amino acids can occur in a plurality ofenantiomeric forms, all these forms and also mixtures thereof (forexample the DL forms) are included above and below. Furthermore, theamino acids may be provided with corresponding protecting groups knownper se.

As evidenced by the continuing research in integrin antagonists and bythe shortcomings of the compounds and methods of the art, there stillremains a need for small-molecule, non-peptidic selective α_(v)β₃ and/orα_(v)β₅ antagonists that display decreased side-effects, improvedpotency, pharmacodynamic and pharmacokinetic properties, such as oralbioavailability and duration of action, over already describedcompounds. Such compounds would prove to be useful for the treatment,prevention, or suppression of various pathologies enumerated above thatare mediated by α_(v)β₃ and/or α_(v)β₅ receptor binding and celladhesion and activation.

In one embodiment, the present invention comprises a class of biphenylintegrin antagonists.

The present invention relates to a class of compounds represented by theFormula I:

or a pharmaceutically acceptable salt, ester or tautomer thereof,wherein:

-   -   A and B are phenyl;    -   n is an integer from 1 to 3;    -   X¹ is selected from O, NR, S, SO, SO₂, CHR, and CH₂, wherein:        -   R is selected from the group consisting of hydrogen, aryl,            and heterocyclyl;    -   X² is selected from the group consisting of alkyl, alkylamino,        aminoalkyl, alkylaminoalkyl, alklthio, thioalkyl,        alkylthioalkyl, alkylsulfonyl, sulfonylalkyl,        alkylsulfonylalkyl, oxyalkyl, alkoxyalkyl, and alkoxy;    -   X³ is C₁-C₆ alkyl;    -   R¹ is selected from the group consisting of pyridinyl and        napthhyridinyl, wherein:        -   either is optionally substituted with a substituent selected            from the group consisting of hydrogen, alkyl, halo, and            amino;    -   R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ are independently selected        from the group consisting of hydrogen, alkyl, alkenyl, alkoxy,        alkoxyalkyl, alkoxycarbonylalkyl, alkylamino, alkylcarbonyl,        alkylheteroaryl, alkylsulfonylalkyl, alkylthio, alkynyl,        aminocarbonylalkyl, cyano, dialkylamino, halo, haloalkoxy,        haloalkyl, hydroxy and hydroxyalkyl; and    -   X³ is independently meta- or para- to the X¹ of the B ring, and        wherein further X³ is ortho-, meta-, or para- to the carboxylic        acid chain of the A ring.

In another embodiment, the invention comprises pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are use in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(b)β_(s) integrins and therefore in another embodimentthe present invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β_(s) integrin.

In another embodiment the invention provides methods of treating orinhibiting pathological conditions associated therewith such asosteoporosis, humoral hypercalcemia of malignancy, Paget's disease,rumor metastasis, solid tumor growth (neoplasia), angiogenesis,including tumor angiogenesis, retinopathy including macular degenerationand diabetic retinopathy, arthritis including rheumatoid arthritis andosteoarthritis, periodontal disease, psoriasis, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as antiviral agentsand antimicrobials. The compounds of the present invention may be usedalone or in combination with other pharmaceutical agents.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β_(s) integrin antagonists; or 3) mixed or dualα_(v)β₃/α_(v)β_(s) antagonists. The present invention includes compoundswhich inhibit the respective integrins and also includes pharmaceuticalcompositions comprising such compounds. The present invention furtherprovides for methods for treating or preventing conditions mediated bythe α_(v)β₃ and/or α_(v)β_(s) receptors in a mammal in need of suchtreatment comprising administering a therapeutically effective amount ofthe compounds of the present invention and pharmaceutical compositionsof the present invention. Administration of such compounds andcompositions of the present invention inhibits angiogenesis, tumormetastasis, tumor growth, osteoporosis, Paget's disease, humoralhypercalcemia of malignancy, retinopathy, macular degeneration,arthritis, periodontal disease, smooth muscle cell migration, includingrestenosis and artherosclerosis, and viral diseases.

The compounds of the present invention further show greater selectivityfor the α_(v)β₃ and/or α_(v)β_(s) integrin than for the α_(v)β₆integrin. It has been found that the selective antagonism of the α_(v)β₃integrin is desirable in that the α_(v)β₆ integrin may play a role innormal physiological processes of tissue repair and cellular turnoverthat routinely occur in the skin and pulmonary tissue, and theinhibition of this function can be deleterious. Therefore, compounds ofthe present invention which selectively inhibit the α_(v)β₃ integrin asopposed to the α_(v)β₆ integrin have reduced side-effects associatedwith inhibition of the α_(v)β₆ integrin.

The present invention relates to a class of compounds represented by theFormula I.

or a pharmaceutically acceptable salts thereof wherein

-   -   X is

-   -   Y is selected from the group consisting of N—R¹, O, and S;    -   A is N or C;    -   R¹ is selected from the group consisting of H, alkyl, aryl,        hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido,        alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,        haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,        arylthiocarbonyl, acyloxymethoxycarbonyl, alkyl optionally        substituted with one or more substituent selected from lower        alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl,        amino, alkoxy, aryl or aryl optionally substituted with one or        more halogen, haloalkyl, lower alkyl, alkoxy, cyano,        alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl,        sulfonic acid, sulfonamide, aryl, fused aryl, monocycle        heterocycles, or fused monocyclic heterocycles, aryl optionally        substituted with one or more substituent selected from halogen,        haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy,        ethylenedioxy, cyano, nitro, alkylthio, alkylsulfonyl, sulfonic        acid, sulfonamide, carboxyl derivatives, amino, aryl, fused        aryl, monocyclic heterocycles and fused monocyclic heterocycle,        monocyclic heterocycles, and monocyclic heterocycles optionally        substituted with one or more substituent selected from halogen,        haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl        derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,        sulfonamide, aryl or fused aryl; or    -   R¹ taken together with R⁸ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower hydroxy,        keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl ester,        and fused phenyl; or    -   R¹ taken together with R⁸ forms a 5 membered heteroaromatic ring        optionally substituted with one or more substituent selected        from lower alkyl, phenyl and hydroxy; or    -   R¹ taken together with R⁸ forms a 5 membered heteroaromatic ring        fused with a phenyl group;    -   R⁸ (when not taken together with R¹) and R⁹ are independently        selected from the group consisting of H, alkyl, alkenyl,        alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino,        amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy,        aryloxycarbonyl, haloalkylcarbonyl, haloalkoxy-carbonyl,        alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl,        cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally        substituted with one or more substituent selected from lower        alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl        derivatives, amino, alkoxy, thio, sulfonyl, aryl, aralkyl, aryl        optionally substituted with one or more substituent selected        from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy,        ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano,        nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino,        alkylamino, dialkylamino, trifluoroalkoxy, trifluoromethyl,        sulfonyl, alkylsulfonyl, haloalkylulfonyl, sulfonic acid,        sulfonamide, aryl, fused aryl, monocyclic heterocycles, fused        monocyclic heterocycles, aryl optionally substituted with one or        more substituent selected from halogen, haloalkyl, lower alkyl,        alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio,        thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy,        amido, acylamino, amino, alkylamino, dialkylamino,        trifluoroalkoxy, trifluoromethylsulfonyl, alkylsulfonyl,        sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic        heterocycles, or fused monocyclic heterocycles, monocyclic        heterocycles, monocyclic heterocycles optionally substituted        with one or more substituent selected from halogen, haloalkyl,        lower alkyl, alkoxy, aryloxy, amino, nitro, hydroxy, carboxyl        derivatives, cyano, alkylthio, alkylsulfonyl, aryl, fused aryl,        monocyclic and bicyclic heterocyclicalkyls, —SO₂R¹⁰ wherein R¹⁰        is selected from the group consisting of alkyl, aryl and        monocyclic heterocycles, all optionally substituted with one or        more substituent selected from the group consisting of halogen,        haloalkyl, alkyl, alkoxy, cyano, nitro, amino, acylamino,        trifluoroalkyl, amido, alkylaminosulfonyl, alkylsulfonyl,        alkylsulfonylamino, alkylamino, dialkylamino,        trifluoromethylthio, trifluoroalkoxy, trifluoromethylsulfonyl,        aryl, aryloxy, thio, alkylthio, and monocyclic heterocycles; and

-   -   wherein R¹⁰ is defined as above; or    -   NR⁸ and R⁹ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S; or    -   X is

-   -   wherein Y′ is selected from the group consisting of alkyl,        cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl        optionally substituted with aryl which can also be optionally        substituted with one or more substituent selected from halogen,        haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or        fused aryl, aryl optionally substituted with one or more        substituent selected from halogen, haloalkyl, hydroxy, alkoxy,        aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy,        or alkyl, alkynyl, alkenyl, —S—R¹¹ and —OR¹¹ wherein R¹¹ is        selected from the group consisting of H, alkyl, aralkyl, aryl,        alkenyl, and alkynyl, or R¹¹ taken together with R⁸ forms a 4-12        membered mononitrogen and monosulfur or monooxygen containing        heterocyclic ring optionally substituted with lower alkyl,        hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused        phenyl, or R¹¹ taken together with R⁸ is thiazole, oxazole,        benzoxazole, or benzothiazole;    -   R⁸ is defined as above; or    -   Y¹ (when Y¹ is carbon) taken together with R⁶ forms a 4-12        membered mononitrogen or dinitrogen containing ring optionally        substituted with alkyl, aryl, keto or hydroxy; or    -   X is

-   -   wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        hydroxy, keto, phenyl, or carboxyl derivatives; and R⁹ is        selected from the group consisting of alkylcarbonyl,        arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,        haloalkyl-carbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,        arylthiocarbonyl, or acyloxymethoxycarbonyl; or    -   X is

-   -   wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogen        containing heterocycle optionally substituted with hydroxy,        keto, phenyl, or alkyl; and    -   R⁹ are both selected from the group consisting of alkylcarbonyl,        arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl,        haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,        arylthiocarbonyl and acyloxymethoxycarbonyl;    -   R², R³ nd R⁴ are independently selected from one or more        substituent selected from the group consisting of H, alkyl,        hydroxy, alkoxy, aryloxy, halogen, haloalkyl, haloalkoxy, nitro,        amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio,        alkylsulfonyl, carboxyl derivatives, trihaloacetamide,        acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic        heterocycles, fused monocyclic heterocycles, and X, wherein X is        defined as above; R⁵, R⁶ and R⁷ are independently selected from        the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl,        carboxyl derivatives, haloalkyl, cycloalkyl, monocyclic        heterocycles, monocyclic heterocycles optionally substituted        with alkyl, halogen, haloalkyl, cyano, hydroxy, aryl, fused        aryl, nitro, alkoxy, aryloxy, alkylsulfonyl, arylsulfonyl,        sulfonamide, thio, alkylthio, carboxyl derivatives, amino,        amido, alkyl optionally substituted with one or more of halo,        haloalkyl, hydroxy, alkoxy, aryloxy, thio, alkylthio, alkynyl,        alkenyl, alkyl, arylthio, alkylssulfoxide, alkylsulfonyl,        arylsulfoxide, arylsulfonyl, cyano, nitro, amino, alkylamino,        dialkylamino, alkylsulfonamide, arylsulfonamide, acylamide,        carboxyl derivatives, sulfonamide, sulfonic acid, phosphonic        acid derivatives, phosphinic acid derivatives, aryl, arylthio,        arylsulfoxide, or arylsulfone all optionally substituted on the        aryl ring with halo alkyl, haloalkyl, cyano, nitro, hydroxy,        carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino,        dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles,        and fused monocyclic heterocycles, monocyclic heterocyclicthio,        monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic        sulfone, which can be optionally substituted with halo,        haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl,        alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl        optionally substituted in one or more positions with halo,        haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy,        ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano,        nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido,        acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy,        trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,        sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused        monocyclic heterocycles.

The compounds according to Formula I can exist in various isomers,enantiomers, tautomers, racemates and polymorphs, and all such forms aremeant to be included.

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagoniing theα_(v)β₃ and/or α_(v)β₃ integrins and therefore in another embodiment thepresent invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β₅ integrin. The invention furtherinvolves treating or inhibiting pathological conditions associatedtherewith such as osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as to antiviralagents, and antimicrobials.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃/α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or α_(v)β₅ receptors in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

The compounds of the present invention further show greater selectivityfor the α_(v)β₃ and/or α_(v)β₅ integrin than for the α_(v)β₆ integrin,it has been found that the selective antagonism of the α_(v)β₃ integrinis desirable in that the α_(v)β₆ integrin may play a role in normalphysiological processes of tissue repair and cellular turnover thatroutinely occur in the skin and pulmonary tissue, and the inhibition ofthis function can be deleterious. Therefore, compounds of the presentinvention which selectively inhibit the α_(v)β₃ integrin as opposed tothe α_(v)β₆ integrin have reduced side-effects associated with inhibtionof the α_(v)β₆ integrin.

The present invention relates to a class of compounds represented by theFormula I.

-   -   or a pharmaceutically acceptable salts thereof wherein    -   X is

-   -   Y is selected from the group consisting of N—R¹, O, and S;    -   y and z are independently selected from an integer selected form        0, 1, 2 and 3;    -   A is N or C;    -   R¹ is selected from the group consisting of H, alkyl, aryl,        hydroxy, alkoxy, cyano, nitro, amino, alkenyl, alkynyl, amido,        alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl        holaalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,        arylthiocarbonyl, acyloxymethoxycarboyl, alkyl optionally        substituted with one or more substituent selected from lower        alkyl, halogen, hydroxyl, haloalkyl, cyano, nitro, carboxyl,        amino, alkoxy, aryl or aryl optionally substituted with one or        more halogen, haloalkyl, lower alkyl, alkoxy, cyano,        alkylsulfonyl, alkylthio, nitro, carboxyl, amino, hydroxyl,        sulfonic acid, sulfonamide, aryl, fused aryl, monocyclic        heterocycles, or fused monocyclic heterocycles, aryl optionally        substituted with one or more substituent selected from halogen,        haloalkyl, hydroxy, lower alkyl, alkoxy, methylenedioxy,        ethylenedioxy, cyano, nitro, alkylthio, alkylsufonyl, sulfonic        acid, sulfonamide, carboxyl derivatives, amino, aryl, fused        aryl, monocyclic heterocycles and fused monocyclic heterocycle,        monocyclic heterocycles, and monocyclic heterocycles optionally        substituted with one or more substituent selected from halogen,        haloalkyl, lower alkyl, alkoxy, amino, nitro, hydroxy, carboxyl        derivatives, cyano, alkylthio, alkylsulfonyl, sulfonic acid,        sulfonamide, aryl or fused aryl; or    -   R¹ taken together with R⁸ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        hydroxy, keto, alkoxy, halo, phenyl, amino, carboxyl or carboxyl        ester, and fused phenyl; or    -   R¹ taken together with R⁸ forms a 5 membered heteroaromatic ring        optionally substituted with one or more substituent selected        from lower alkyl, phenyl and hydroxy; or    -   R¹ taken together with R⁸ forms a 5 membered heteroaromatic ring        fused with a phenyl group;    -   R⁸ (when not taken together with R¹) and R⁹ are independently        selected from the group consisting of H, alkyl, alkenyl,        alkynyl, aralkyl, amino, alkylamino, hydroxy, alkoxy, arylamino,        amido, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxy,        aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,        alkylthiocarbonyl, arylthiocarbonyl, acyloxymethoxycarbonyl,        cycloalkyl, bicycloalkyl, aryl, acyl, benzoyl, alkyl optionally        substituted with one or more substituent selected from lower        alkyl, halogen, hydroxy, haloalkyl, cyano, nitro, carboxyl        derivatives, amino, alkoxy, thio, alkylthio, sulfonyl, aryl,        aralkyl, aryl optionally substituted with one or more        substituent selected from halogen, haloalkyl, lower alkyl,        alkoxy, methylenedioxy, ethylenedioxy, alkylthio, haloalkylthio,        thio, hydroxy, cyano, nitro, carboxyl derivatives, aryloxy,        amido, acylamino, amino, alkylamino, dialkylamino,        trifluoroalkoxy, trifluoromethyl, sulfonyl, alkylsulfonyl,        haloalkylsulfonyl, sulfonic acid, sulfonamide, aryl, fused aryl,        monocyclic heterocycles, fused monocyclic heterocycles, aryl        optionally substituted with one or more substituent selected        from halogen, haloalkyl, lower alkyl, alkoxy, methylenedioxy,        ethylenedioxy, alkylthio, haloalkylthio, thio, hydroxy, cyano,        nitro, carboxyl derivatives, aryloxy, amido, acylamino, amino,        alkylamino, dialkylamino, trifluoroalkoxy,        trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,        sulfonamide, aryl, fused aryl, monoyclic heterocycles, or fused        monocyclic heterocycles, monocyclic heterocycles, monocyclic        heterocycles optionally substituted with one or more substituent        selected from halogen, haloalkyl, lower alkyl, alkoxy, aryloxy,        amino, nitro, hydroxy, carboxyl derivatives, cyano, alkylthio,        alkylsulfonyl, aryl, fused aryl, monocyclic and bicyclic        heterocyclicalkyls, —SO₂R¹⁰ wherein R¹⁰ is selected from the        group consisting of alkyl, aryl and monocyclic heterocycles, all        optionally substituted with one or more substituent selected        faun the group consisting of halogen, haloalkyl, alkyl, alkoxy,        cyano, nitro, amino, acylamino, trifluoroalkyl, amido,        alkylaminosulfonyl, alkylsulfonyl, alkylsulfonylamino,        alkylamino, dialkylamino, trifluoromethylthio, Trifluoroalkoxy,        trifluoromethylsulfonyl, aryl, aryloxy, thio, and monocyclic        Heterocycles; and

-   -   wherein R¹⁰ is defined as above; or    -   NR⁸ and R⁹ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S; or    -   X is

-   -   wherein Y′ is selected from the group consisting of alkyl,        cycloalkyl, bicycloalkyl, aryl, monocyclic heterocycles, alkyl        optionally substituted with aryl which can also be optionally        substituted with one or more substituent selected from halo,        haloalkyl, alkyl, nitro, hydroxy, alkoxy, aryloxy, aryl, or        fused aryl, aryl optionally substituted with one or more        substituent selected from halo, haloalkyl, hydroxy, alkoxy,        aryloxy, aryl, fused aryl, nitro, methylenedioxy, ethylenedioxy,        or alkyl, alkynyl, alkenyl, —SR—R¹¹ and —OR¹¹ wherein R¹¹ is        selected from the group consisting of H, aralkyl, aryl, alkenyl,        and alkynyl, or R¹¹ taken together with R⁸ forms a 4-12 membered        mononitrogen and monosulfur or monooxygen containing        heterocyclic ring optionally substituted with lower alkyl,        hydroxy, keto, phenyl, carboxyl or carboxyl ester, and fused        phenyl, or R¹¹ taken together with R⁸ is thiazole, oxazole,        benzoxazole, or benzothiazole;    -   R⁸ is defined as above; or    -   Y¹ (when Y¹ is carbon) taken together with R⁸ forms a 4-12        membered mononitrogen or dinitrogen containing ring optionally        substituted with alkyl, aryl, keto or hydroxy; or    -   X is

-   -   wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        hydroxy, keto, phenyl, or carboxyl derivatives; and R⁹ is        selected from the group consisting of alkylcarbonyl,        arylcarbonyl, alkoxycarbornyl, aryloxycarbonyl,        haloalkylcarbonyl, haloalkoxycarbonyl, alkylthiocarbonyl,        arylthiocarbonyl, or acyloxymethoxycarbonyl; or    -   X is

-   -   wherein R¹ and R⁸ taken together form a 5-8 membered dinitrogen        containing heterocycle optionally substituted with hydroxy,        keto, phenyl, or alkyl; and R⁹ are both selected from the group        consisting of alkylcarbonyl, arylcarbonyl, alkoxycarbonyl,        aryloxycarbonyl, haloalkylcarbonyl, haloalkoxycarbonyl,        alkylthiocarbonyl, arylthiocarbonyl and acyloxymethoxycarbonyl;    -   R², R³ and R⁴ are independently selected from one or more        substituent selected from the group consisting of H, alkyl,        hydroxy, alkoxy, aryloxy halogen, haloalkyl, haloalkoxy, nitro,        amino, alkylamino, acylamino, dialkylamino, cyano, alkylthio,        alkylsulfonyl, carboxyl derivatives, trihaloacetamide,        acetamide, aryl, fused aryl, cycloalkyl, thio, monocyclic        heterocycles, fused monocyclic heterocycles, and X, wherein X is        defined as above;    -   R⁵, R⁶ and R⁷ are independently selected from the group        consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, carboxyl        derivatives, haloalkyl, cycloalkyl, monocyclic heterocycles,        monocycli hetemeyeles optionally substituted with alkyl,        halogen, halonikyl, cyano, hydroxy, aryl, fused aryl, nitro,        alkoxy, aryloxy alkylsulthnyl aylsulfortyl, staltbnamide, thio,        alkylthio carboxyl derivatives, amino, amido, alkyl optionally        substituted with one or more of halo, haloalkyl, hydroxy,        alkoxy, aryloxy, thio, alkylthio, alkynyl, alkenyl, alkyl,        arylthio, alkylsulfoxide, alkylaulfonyl, arylsulfoxide,        arylsulfonyl, cyano, nitro, amino, alkylamino, dialkylamino,        alkylsulfonamide, arylsufonamide, acylamide, carboxyl        derivatives, sulfonamide, Sulfonic acid, phosphonic acid        derivatives phosphinic acid derivatives, aryl, arylthio,        arylsulfoxide, or arylsulfone all optionally substituted on the        aryl ring with halo, alkyl, haloalkyl, cyano, nitro, hydroxy,        carboxyl derivatives, alkoxy, aryloxy, amino, alkylamino,        dialkylamino, amido, aryl, fused aryl, monocyclic heterocycles,        and fused monocyclic heterocycles, monocyclic heterocyclicthio,        monocyclic heterocyclicsulfoxide, and monocyclic heterocyclic        sulfone, which can be optionally substituted with halo,        haloalkyl, nitro, hydroxy, alkoxy, fused aryl, or alkyl,        alkylcarbonyl, haloalkylcarbonyl, and arylcarbonyl, aryl        optionally substituted in one or more positions with halo,        haloalkyl, alkyl, alkoxy, aryloxy, methylenedioxy,        Ethylenedioxy, alkylthio, haloalkythio, thio, hydroxy, cyano,        nitro, acyloxy, carboxyl derivatives, carboxyalkoxy, amido,        acylamino, amino, alkylamino, dialkylamino, trifluoroalkoxy,        trifluoromethylsulfonyl, alkylsulfonyl, sulfonic acid,        sulfonamide, aryl, fused aryl, monocyclic heterocycles and fused        monocyclic heterocycles.

The compounds according to Formula I can exist in various isomers,enantiomers, tautomers, racemates and polymorphs, and all such forms aremeant to be included.

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅ integrins and therefore in another embodiment thepresent invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v) ₅ integrin. The invention furtherinvolves treating or inhibiting pathological conditions associatedtherewith such as osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as antiviral agents,and antimicrobials.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃/α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes Pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or α_(v)β₃ receptors in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

Further, it has been found that the selective antagonism of the α_(v)β₃integrin is desirable in that the α_(v)β₆ integrin may play a role innormal physiological processes of tissue repair and cellular turnoverthat routinely occur in the skin and pulmonary tissue, and α_(v)β₈ mayplay a role in the regulation of growth in the human pathway. Therefore,compounds which selectively inhibit the α_(v)β₃ integrin as opposed tothe α_(v)β₆ and/or the α_(v)β₈ integrin have reduced side-effectsassociated with inhibition of the α_(v)β₆ and/or the α_(v)β₈ integrin.It is therefore another object of the present invention to providecompounds that are selective antagonists of α_(v)β₃ and/or α_(v)β₅ asopposed to α_(v)β₆, and it is yet another object of the presentinvention to provide compounds that are selective antagonists of CVD3and/or α_(v)β₅ as opposed to α_(v)β₈.

The present invention relates to a class of compounds represented by theFormula 1, 2

-   -   or a pharmaceutically acceptable salt thereof, wherein 3

-   -   is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring,        optionally containing 1 to 4 heteroatoms, selected from the        group consisting of O, N or S; optionally saturated or        unsaturated, optionally substituted with one or more substituent        selected from the group consisting of alkyl, haloalkyl, aryl,        heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro,        alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino,        alkylsulfonamide, acyl, acylamino, sulfone, sulfonamide, allyl,        alkenyl, methylenedioxy, ethylenedioxy, alkynyl, carboxamide,        cyano, and —(CH₂)_(n)COR wherein n is 0-2 and R is hydroxy,        alkoxy, alkyl or amino;    -   A¹ is a 5-9 membered monocyclic or 7-14 membered polycyclic        heterocycle of the formula 4

-   -   containing at least one nitrogen atom and optionally 1 to 4        heteroatoms or groups selected from O, N, S, SO₂ or CO;        optionally saturated or unsaturated; optionally substituted by        one or more Rk selected from the group consisting of hydroxy,        alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino,        alkylamino, halogen, acylamino, sulfonamide and —COR wherein R        is hydroxy, alkoxy, alkyl or amino; 5

-   -   include the following heterocyclic ring systems containing at        least one nitrogen atom:

-   -   wherein Z_(n) is H, alkyl, alkoxy, hydroxy, amine, alkylamine,        dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or        haloalkyl and R¹ is H, alkyl, alkoxyalkyl, acyl, haloalkyl or        alkoxycarbonyl. More specifically some examples of embodiments        include pyridylamino, imidazolylamino, morpholinopyridine,        tetrahydronaphthyridine, oxazolylamino, thiazolylamino,        pyrimidinylamino, quinoline, isoquinoline, tetrahydroquinoline,        imidazopyridine, benzimidazole, pyridone quinolone.

The following heteroaryls include the ring systems described above.

For the pyridyl derived heterocycle, the substituents X₄ and X₅ areselected from the group consisting of H, alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups. Inanother embodiment of the invention, the substituents X4 and X₅ can bemethyl, methoxy, amine, methylamine, trifluoromethyl, dimethylamine,hydroxy, chloro, bromo, fluoro and cyano. X₆ may preferentially be H,alkyl, hydroxy, halogen, alkoxy and haloalkyl. Alternately, the pyridylring can be fused with a 4-8 membered ring, optionally saturated orunsaturated. Some examples of these ring systems includetetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline,morpholinopyridine, imidazo-pyridine and the like. The monocyclic ringsystems such as imidazole, thiazole, oxazole, pyrazole, and the like,may contain an amino or alkylamino substituent at any position withinthe ring.

In another embodiment of the present invention, when Z₁ of Formula I isCO or SO₂, the linkage A¹-Z₂ of Formula I includes the heterocyclederived ring systems such as: pyridine, imidazole, thiazole, oxazole,benzimidazole, imidazopyridine and the like.

Other heterocycles for A¹-Z₂ of the present invention include

-   -   wherein X4 is as defined above. or    -   A¹ is

-   -   wherein Y¹ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl; aryl;        hydroxy; alkoxy; cyano; alkenyl; alkynyl; amido; alkylcarbonyl;        arylcarbonyl; alkoxycarbonyl; aryloxycarbonyl;        haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl;        arylthiocarbonyl; acyloxymethoxycarbonyl;    -   R² taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester, and fused phenyl; or    -   R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated; or    -   R² taken together with R⁷ forms a 5 membered heteroaromatic ring        fused with a aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; alkenyl;        alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino;        amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy;        aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;        alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;        cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl; or    -   NR⁷ and R⁸ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S;    -   R⁵ is selected from the group consisting of H and alkyl.    -   As evidenced by the continuing research in integrin antagonists        and by the shortcomings of the compounds and methods of the art,        there still remains a need for non-peptidic selective α_(v)β₃        and/or α_(v)β₅ antagonist that displays decreased side-effects,        and improved potency, pharmacodynamic, and pharmacokinetic        properties, such as oral bioavailability and duration of action,        over already described compounds. Such compounds would prove to        be useful for the treatment, prevention, or suppression of        various pathologies enumerated above that are mediated by        α_(v)β₃ and/or α_(v)β₅ receptor binding and cell adhesion and        activation.

The compounds of the present invention further show greater selectivityfor the α_(v)β₃ and/or α_(v)β₅ integrin than for the α_(v)β₆ integrin.It has been found that the selective antagonism of the α_(v)β₃ integrinis desirable in that the α_(v)β₆ integrin may play a role in normalphysiological processes of tissue repair and cellular turnover thatroutinely occur in the skin and pulmonary tissue, and the inhibition ofthis function can be deleterious (Huang et al., Am J Respir Cell MolBiol 1998, 19(4): 636-42). Therefore, compounds of the present inventionwhich selectively inhibit the α_(v)β₃ integrin as opposed to the α_(v)β₆integrin have reduced side effects associated with inhibition of theα_(v)β₆ integrin.

The compounds of the present invention comprise the R-isomers of thecarbon of the beta amino acid. Other isomers may result from additionalchiral centers, depending on the substitution of the parent structure.

The present invention relates to a class of compounds represented by theFormula I:

-   -   or a pharmaceutically acceptable salt or tautomer thereof;    -   wherein X has the structure of formula Ia:

-   -   and wherein X is optionally substituted with one or more        substituents independently selected from the group consisting of        OH, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,        alkoxy, dialkylamino, thioalkyl, cycloalkyl, CN, NO₂, and        halogen; or, in an alternative embodiment, X is a monocyclic        heterocycle containing a N as shown, optionally substituted with        one to ten, or alternatively 1-3 substituents independently        selected from the group consisting of H, OH, alkyl, CN, NO₂,        aminoalkyl, halogen, haloalkyl, and alkoxy;    -   Y is a six-membered aryl; or alternatively, a six-membered        heterocycyl ring containing 1 to 2 heteroatoms, selected from        the group consisting of O, N or S; wherein the six-membered ring        is optionally substituted with one or more substitutents        independently selected from the group consisting of OH, alkyl,        alkoxy, NO₂, NH₂, CN, NHCOCF₃, COCF₃, haloalkyl, aryl,        methylenedioxy, ethylenedioxy, heterocycyl, halogen,        alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino,        arylamino, alkylsulfonamido, acyl, acylamino, alkylsulfone,        sulfonamido, allyl, alkenyl, alkynyl, carboxamide NHCOCF₃, and        —(CH₂)_(m)COR²;    -   m is a number from 0 to 2;    -   R² is hydroxy, alkoxy, or amino;    -   Z is a 5 to 6-membered monocyclic, or a 9 to 12-membered        bicyclic, aryl or heterocycyl ring; optionally containing 1 to 5        heteroatoms selected from the group consisting of O, N or S;        optionally saturated or unsaturated, optionally substituted with        one or more substituents selected from the group consisting of        alkyl, haloalkyl, aryl, heterocycyl, arylalkyl, aryloxy,        phenethyl, arylsulfone, halogen, alkoxyalkyl, aminoalkyl,        cycloalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl,        amino, alkylamino, arylamino, alkylsulfonamido, acyl, acylamino,        alkylsulfone, sulfonamido, allyl, alkenyl, methylenedioxy,        ethylenedioxy, alkynyl, carboxamide, cyano, NHCOCF₃, and        —(CH₂)_(m)COR²; wherein the aryl and heterocycyl substituents        are also optionally substituted with one or more substituents        selected from the group consisting of alkyl, cycloalkyl,        haloalkyl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro,        alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino,        alkylsulfonamido, acyl, acylamino, alkylsulfone, sulfonamido,        allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,        carboxamide, cyano, and —(CH₂)_(m)COR²;    -   Q is NH or CH₂;    -   R is selected from the group consisting of OH, alkoxy, and NHR³;    -   R³ is H or an alkyl group;    -   R¹ is H, CN, NO₂, acyl, haloalkyl, alkenyl, alkynyl, or alkyl;    -   n is 0, 1, or 2,    -   and carbon atom 3 is in the (R) conformation.

It is another embodiment of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅, integrins and therefore in another embodimentthe present invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β₅ integrin. The invention furtherembodies treating or inhibiting pathological conditions associatedtherewith such as osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis and osteoarthritis, periodontal disease, psoriasis,smooth muscle cell migration and restenosis in a mammal in need of suchtreatment. Additionally, such pharmaceutical agents are useful asantiviral agents, and antimicrobials. The compounds of the presentinvention may be used alone or in combination with other pharmaceuticalagents.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃/α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or 60_(v)β₅ receptors in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

The compounds of the present invention further show greater selectivityfor the α_(v)β₃ and/or α_(v)β₅ integrin than for the α_(v)β₆ integrin.It has been found that the selective antagonism of the α_(v)β₃ integrinis desirable in that the α_(v)β₆ integrin may play a role in normalphysiological processes of tissue repair and cellular turnover thatroutinely occur in the skin and pulmonary tissue, and the inhibition ofthis function can be deleterious. Therefore, compounds of the presentinvention which selectively inihibit the α_(v)β₃ integrin as opposed tothe α_(v)β₆ integrin have reduced side-effects associated withinhibition of the αvβ₆ integrin.

The present invention relates to a class of compounds represented by theFormula I

-   -   or a pharmaceutically acceptable salt thereof, wherein    -   A¹ is a 5-9 membered monocyclic or 7-12 membered bicyclic        heterocycle of the formula

-   -   containing at least one nitrogen atom and optionally 1 to 3        heteroatoms, selected from the group consisting of O, N or S;        optionally saturated or unsaturated; optionally substituted by        one or more R^(k) selected from the group consisting of hydroxy,        alkyl, cycloalkyl, alkoxy, alkoxyalkyl, thioalkyl, cyano, amino,        alkylamino, halogen, acylamino, sulfonamide and —COR wherein R        is hydroxy, alkoxy, alkyl or amino;    -   or A¹ is

-   -   wherein Y¹ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl;        cycloalkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl;        amido; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl;        aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;        alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;    -   R² taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester, and fused phenyl;    -   or R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated;    -   or R² taken together with R⁷ forms a 5 membered heteroaromatic        ring fused with a aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; alkenyl;        alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino;        amido, alkylcarbonyl, arylcarbonyl; alkoxycarbonyl; aryloxy;        aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;        alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;        cycloalkyl; bicycloalkyl; aryl; acyl; benzoyl;    -   or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S;    -   R⁵ is selected from the group consisting of H, cycloalkyl and        alkyl; 5    -   A¹ is

-   -   wherein Y² is selected from the group consisting of alkyl;        cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;    -   Z₁ is selected from the group consisting of CH₂, O, CH₂O,        NR_(k), CO, S, SO, CH(OH) and SO₂, wherein R_(k) is selected        from H or lower alkyl;    -   Z₂ is a 1-5 carbon linker optionally containing one or more        heteroatom selected from the group consisting of O, S and N;        alternatively Z₁-Z₂ may further contain a carboxamide, sulfone,        sulfonamide, alkenyl, alkynyl, or acyl group;    -   wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionally        substituted by alkyl, cycloalkyl, alkoxy, thioalkyl,        alkylsulfone, aryl, alkoxyalkyl, hydroxy, alkylamino,        heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen, haloalkyl        or acylamino;    -   n is an integer 0, 1 or 2;    -   R^(c) is selected from the group consisting of hydrogen; alkyl;        cycloalkyl; halogen, hydroxy, nitro, alkoxy, amino, haloalkyl,        aryl, heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl,        thioalkyl, alkylamino, arylamino, alkylsulfonylamino, acyl,        acylamino, sulfonyl, sulfonamide, allyl, alkenyl,        methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy,        alkoxycarbonyl, carboxamido, cyano, and —(CH₂)_(n)COR wherein n        is 0-2 and R is selected from hydroxy, alkoxy, alkyl and amino;    -   X is selected from the group consisting of O, CO, SO₂, NR^(m)        and (CHR^(p))_(n); wherein R^(p) and R^(m) are H or alkyl;    -   R^(b) is X₃—R^(h) wherein X₃is selected from the group        consisting of O, S and NR¹ wherein R^(h) and R^(j) are        independently selected from the group consisting of H, alkyl,        acyl, aryl, aralkyl and alkoxyalkyl; and    -   It is another object of the invention to provide pharmaceutical        compositions comprising compounds of the Formula I. Such        compounds and compositions are useful in selectively inhibiting        or antagonizing the α_(v) β₃ and/or α_(v) β₅ integrin(s) and        therefore in another embodiment the present invention relates to        a method of selectively inhibiting or antagonizing the α_(v) β₃        and/or α_(v) β₅ integrin(s). The invention further involves        treating or inhibiting pathological conditions associated        therewith such as osteoporosis, humoral Hypercalcemia of        malignancy, Paget's disease, tumor metastasis, solid tumor        growth (neoplasia), angiogenesis, including tumor angiogenesis,        retinopathy including macular degeneration and diabetic        retinopathy, arthritis, including rheumatoid arthritis,        periodontal disease, psoriasis, smooth muscle cell migration        including restenosis or atherosclerosis in a mammal in need of        such treatment. Additionally, such pharmaceutical agents are        useful as antiviral agents, antifungals and antimicrobials. The        compounds of the present invention may be used alone or in        combination with other pharmaceutical agents.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃ /α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or α_(v)β₅ receptors in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

Further, it has been found that the selective antagonism of the α_(v)β₃integrin is desirable in that the α_(v)β₆ integrin may play a role innormal physiological processes of tissue repair and cellular turnoverthat routinely occur in the skin and pulmonary tissue, and α_(v)β₈ mayplay a role in the regulation of growth in the human pathway. Therefore,compounds which selectively inihibit the α_(v)β₃ integrin as opposed tothe α_(v)β₆ and/or the α_(v)β₈ integrin have reduced side-effectsassociated with inhibition of the α_(v)β₆ and/or the α_(v)β₈ integrin.It is therefore another object of the present invention to providecompounds that are selective antagonists of α_(v)β₃ as opposed toα_(v)β₆, and it is yet another object of the present invention toprovide compounds that are selective antagonists of α_(v)β₃ and/orα_(v)β₅ as opposed to α_(v)β₈.

The present invention relates to a class of compounds represented by theFormula I

-   -   or a pharmaceutically acceptable salt thereof, wherein

-   -   is a 4-8 membered monocyclic ring or a 7-12 membered bicyclic        ring, which ring is optionally saturated or unsaturated; which        ring is optionally substituted with one or more substituent        selected from the group consisting of alkyl, haloalkyl, aryl,        heteroaryl, halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro,        alkoxy, hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino,        alkylsulfonamide, acyl, acylamino, alkylsulfone, sulfonamide,        allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,        carboxamide, cyano, and —(C₂)_(n) COR wherein n is 0-2 and R is        hydroxy, alkoxy, alkyl or amino;

A¹ is a 5-9 membered monocyclic ring or 7-12 membered bicyclicheterocycle ring of the formula

-   -   containing at least one nitrogen atom and optionally containing        1 to 4 heteroatoms selected from the group consisting of O, N,        S, SO₂ and CO; optionally saturated or unsaturated; optionally        substituted by one or more R^(k) is selected from the group        consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl,        cyano, amino, alkylamino, haloalkyl, halogen, acylamino,        sulfonamide and —COR wherein R is hydroxy, alkoxy, alkyl or        amino;    -   or A¹ is

-   -   wherein Y¹ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl; aryl;        hydroxy; alkoxy; cyano; amido; alkylcarbonyl; arylcarbonyl;        alkoxycarbonyl; aryloxycarbonyl; haloalkylcarhonyl;        haloalkoxycarbonyl; alkylthiocarbonyl, arylthiocarbonyl;        acyloxymethoxycarbonyl;    -   R²taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester;    -   or R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated;    -   or R² taken together with R⁷ forms a 5 membered heterearomatic        ring fused with a aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; aralkyl; amino;        alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl,        arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl;        haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl;        arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl;        bicycloalkyl; aryl; acyl; benzoyl;    -   or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S; R⁵ is selected from the group consisting of H, and alkyl;        or    -   A is

-   -   wherein Y is selected from the group consisting of alkyl;        cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;    -   Z₁ is selected from the group consisting of CH₂, CH₂O, O, NH,        NR_(k), CO, S, SO, CH(OH), and SO₂, wherein R_(k) (is selected        from H or lower alkyl;    -   Z₂ is a 1-5 carbon linker optionally containing one or more        heteroatom selected from the group consisting of O, S and N;        alternatively Z₁-Z₂ may further contain a carboxamide, sulfone,        oxime, sulfonamide, alkenyl, alkynyl, or acyl group;    -   wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionally        substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,        alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,        carboxyalkyl, halogen, haloalkyl or acylamino;    -   wherein Z₂-Z₁ is attached to

-   -   at the para or meta position relative to the X₁ substituent;    -   n is an integer 0, 1 or 2;    -   R^(c) is selected from the group consisting of hydrogen; alkyl;        halogen, hydroxy nitro, alkoxy, amino, haloalkyl, aryl,        heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl,        alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino,        sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy,        ethylenedioxy, alkynyl alkynylalkyl, carboxy, alkoxycarbonyl,        carboxamido, cyano and —(CH₂)_(n)—COR wherein n is 0-2 and R is        selected from hydroxy, alkoxy, alkyl and amino;    -   X¹ is selected from the group consisting of —O—, CO, SO₂, NR^(m)        and (CHR^(p))_(q); wherein R^(m) is H or alkyl; R^(p) is alkoxy        or hydroxy and q is 0 or 1;    -   X₂ is selected from the group consisting of —CHR^(c)—, CO, SO₂,        O, NR^(f) and S;    -   R^(c) is selected from the group consisting of H, alkyl, hydroxy        and alkoxy; R^(f) is H or alkyl;

X or Y are independently selected from the group consisting of —CR^(g)—or —N— wherein R^(g) is selected from the group consisting of H, alkyl,haloalkyl, fluoro, alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl,alkylsulfone, heteroaralkyl, hydroxy, alkoxy, hydroxyalkyl, andcarboxyalkyl;

The group X—X₂—Y optionally contains a moiety selected from the groupconsisting of acyl, alkyl, amino, ether, thioether, sulfone, and olefin:

-   -   forms a 3-8 membered monocyclic ring system; or an 8-11 membered        bicyclic system; optionally saturated or unsaturated; the        monocyclic ring system optionally containing 1-2 heteroatoms        selected from N, O and S; the bicyclic ring system optionally        containing 1-4 heteroatoms selected from N, O, S or optionally        containing the group such as SO₂ or CO); and optionally        substituted with one or more substituent selected from the group        consisting of alkyl, halogen, cyano, carboalkoxy, haloalkyl,        alkoxyalkyl, alkylsulfone, aryl, heteroaryl, aralkyl,        heteroaralkyl or alkoxy;    -   R^(b) is X₃-R^(h) wherein X₃ is selected from the group        consisting of O, S and NR^(j) wherein R^(h) and R^(j) are        independently selected from the group consisting of H, alkyl,        acyl, aryl, aralkyl and alkoxyalkyl; and    -   and n is 0, 1 or 2.

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅ integrin(s) and therefore in another embodimentthe present invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β₅ integrin(s). The inventionfurther involves treating or inhibiting pathological conditionsassociated therewith such as osteoporosis, immoral hypercalcemia ofmalignancy, Paget's disease, tumor metastasis, solid tumor growth(neoplasia), angiogenesis, including tumor angiogenesis, retinopathyincluding macular degeneration and diabetic retinopathy, arthritis,including rheumatoid arthritis. periodontal disease, psoriasis, smoothmuscle cell migration including restenosis or atherosclerosis in amammal in need of such treatment. Additionally, such pharmaceuticalagents are useful as antiviral agents, antifungals and antimicrobials.The compounds of the present invention may be used alone or incombination with other pharmaceutical agents.

The compounds of this invention are 1) α_(v)β₃ integrin antagonists; or2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃/α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or α_(v)β₅ receptors in a mammal in need of such treatmentcomprising, administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

The compounds of the present invention further show greater selectivityfor the α_(v)β₃ and/or α_(v)β₅ integrin than for the α_(v)β₆ integrin.It has been found that the selective antagonism of the α_(v)β₃ integrinis desirable in that the α_(v)β₆ integrin may play a role in normalphysiological processes of tissue repair and cellular turnover thatroutinely occur in the skin and pulmonary tissue, and the inhibition ofthis function can be deleterious. Therefore, compounds of the presentinvention which selectively inihibit the α_(v)β₃ integrin as opposed tothe α_(v)β₆ integrin have reduced side-effects associated with inhibtionof the α_(v)β α_(v)β₆ integrin.

The present invention relates to a class of compounds represented by theFormula I.

-   -   or a pharmaceutically acceptable salt thereof, wherein

-   -   is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring,        optionally saturated or unsaturated, optionally substituted with        one or more substituent selected from the group consisting of        alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl,        aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl,        amino, alkylamino, arylamino, alkylsulfonamide, acyl, acylamino,        alkylsulfone, sulfonamide, alkylsulfoxide, allyl, alkenyl,        methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and        —(CH₂)_(n) COR wherein n is 0-2 and R is hydroxy, alkoxy, alkyl        or amino;    -   A¹ is a 5-9 membered monocyclic or 7-12 membered bicyclic        heterocycle of the formula

-   -   containing at least one nitrogen atom and optionally 1 to 3        additional heteroatoms, selected from the group consisting of O,        N, S, CO, or SO₂ optionally saturated or unsaturated; optionally        substituted by one or more R^(k) selected from the group        consisting of hydroxy, alkyl, cycloalkyl, alkoxy, alkoxyalkyl,        thioalkyl, cyano, amino, alkylamino, halogen, acylamino,        sulfonamide and —COR wherein R is hydroxy, alkoxy, alkyl or        amino;    -   or A¹ is

-   -   wherein Y₁ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl;        cycloalkyl; aryl; hydroxy; alkoxy; cyano; alkenyl; alkynyl;        amino; alkylcarbonyl; arylcarbonyl; alkoxycarbonyl;        aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;        alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;    -   R² taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester, and fused phenyl;    -   or R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated;    -   or R² taken together with R⁷ forms a 5 membered heteroaromatic        ring fused with an aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; alkenyl;        alkynyl; aralkyl; amino; alkylamino; hydroxy; alkoxy; arylamino;        amido, alkylcarbonyl; arylcarbonyl; alkoxycarbonyl, aryloxy,        aryloxycarbonyl; haloalkylcarbonyl; haloalkoxycarbonyl;        alkylthiocarbonyl; arylthiocarbonyl; acyloxymethoxycarbonyl;        cycloalkyl; bicyclocalkyl; aryl; acyl; benzoyl;    -   or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contins a heteroatom selected from the group consisting of O, N        and S;    -   R⁵ is selected from the group consisting of H, hydroxy, alkoxy,        cycloalkyl, and alkyl; or

-   -   wherein Y² is selected from the ggroup consisting of alkyl;        cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;    -   Z₁ is selected from the group consisting of CH₂, O, CH₂O,        NR_(k), CO, S, SO, CH(OH) and SO₂, wherein Rk is selected from H        or lower alkyl;    -   Z₂ is a 1-5 carbon linker optionally containing one or more        heteroatom selected from the group consisting of O, S and N;        alternatively Z₁-Z₂ may further contain a Carboxamide, sulfone,        sulfonamide, alkenyl, alkynyl, or acyl group;    -   wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionally        substituted by alkyl, cycloalkyl, alkoxy, thioalkyl,        alkylsulfone, aryl, arylsulfone, alkoxyalkyl, hydroxy,        alkylamino, heteroaryl, alkenyl, alkynyl, carboxyalkyl, halogen,        haloalkyl, or acylamino;    -   n is an integer 1 or 2;    -   R^(c) is selected from the group consisting of hydrogen, alkyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, halogen, hydroxy,        nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl,        aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino,        alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide,        allyl, alkenyl, methylenedioxy, ethylenedioxy; alkynyl,        alkynylalkyl, carboxy, alkoxycarbonyl, carboxamido, cyano, and        —(CH₂)_(n)COR wherein n is 0-2 and R is selected from hydroxy,        alkoxy, alkyl and amino;    -   X is selected from the group consisting of —CHR^(e)—, —NR^(f)—,        —O—, —S—, —SO₂—, and —CO— wherein R^(c) is H, lower alkyl,        alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl,        haloalkyl, thioalkyl or aryl; wherein when R^(e) is hydroxy, the        hydroxy group can optionally form a lactone with the carboxylic        acid function of the chain; wherein R^(f) is selected from the        group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl,        aralkyl, arakylheteroaryl, and haloalkyl;    -   Y is selected from the group consisting of (CH₂)_(p), —CR⁹—,        —NR⁹, CO and SO², wherein R⁹ is selected from the group        consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl,        heteroaryl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, and        carboxyalkyl; wherein p is 0 or 1;    -   optionally the group X-Y can contain a moiety selected from the        group consisting of acyl, alkyl, sulfonyl, amino, ether,        thioether, carboxamido, sulfonamido, aminosulfonyl and olefins;    -   Y³ and Y⁴ are independently selected from the group consisting        of alkyl, haloalkyl, hydroxy, alkoxy, cyano, halogen, aralkyl,        heteroaralkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl,        alkylsulfone, alkene or alkyne; wherein the alkyl group        optionally contains one or more heteroatoms selected from the        group consisting of N, O, and S;    -   alternately, when Y³ is an aryl or a heteroaryl, Y⁴ may be an        aryl, heteroaryl, alkene, alkyne, alkoxy, hydroxy, cyano,        alkoxyalkyl or an alkylsulfone;    -   Y⁵ is C;    -   Optionally, Y³, Y⁴ and Y⁵ may form a sulfone (SO₂) group;    -   or Y³ taken together with Y⁴ forms a 3-8 membered monocyclic or        a 7-11 membered bicyclic ring, optionally containing one or mare        double bonds, optionally containing one or more heteroatom or        functional group selected from O, NR⁹, S, CO or SO₂, optionally        substituted with one or more substituent selected from the group        consisting of alkyl, heteroalkyl, hydroxy, halogen, lialoalk,O,        alkoxy, alkyne, cyano, alkylsulfone, sulfonamide, aryl,        heteroaryl, arakylaryl, heteroarakylarylcarboalkoxy and        carboxyalkyl;    -   R^(b) is X₂—R^(h) wherein X₂ is selected from the group        consisting of O, S and NR¹ wherein R^(h) and R^(j) are        independently selected from the group consisting of H, alkyl,        aryl, aralkyl, heteroalkyl, heteroaryl, heteroarakylaryl, acyl,        and alkoxyalkyl;

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ and/or α_(v)β₅ integrins and therefore in another embodiment thepresent invention relates to a method of selectively inhibiting orantagonizing the α_(v)β₃ and/or α_(v)β₅ integrin. The invention furtherinvolves treating or inhibiting pathological conditions associatedtherewith such as osteopbrosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cellmigration and restenosis in a mammal in need of such treatment.Additionally, such pharmaceutical agents are useful as antiviral agents,and antimicrobials. The compounds of the present invention may be usedalone or in combination with other pharmaceutical agents.

The present invention as a first object provides compounds of thefollowing formula (I)

-   -   or a pharmaceutically acceptable salt, prodrug or ester thereof,        wherein    -   G is selected from the group consisting of:

-   -   wherein Q is NH or O and Q′ is H, C₁-C₆alkyl, phenyl, or        phenyl-C₁-C₄-alkyl;

-   -   wherein R′ and R″ are independently H or C₁-C-₄ alkyl;    -   B is a C₁C₄ alkyl or a C₂-C₄ alkenyl;    -   A is CH₂, O, S(O)_(n) wherein n is zero, 1 or 2, NH, a group        CON(R′″) or N(R′″)CO wherein R′″ is hydrogen or CH₃;

R1 is selected from the group consisting of H, C₁-C₄ alkyl, C₁-C₄alkoxy, OH, halogen, and CF₃;

-   -   X is C═O or completes a single bond;    -   R₂ is selected from the group consisting of H, C₁-C₄ alkyl,        C₃-C₇ cycloalkyl, C₁-C₄-alkylcycloalkyl; aryl unsubstituted or        optionally substituted by one to three Substituents        independently selected from halogen, CF₃, C₁-C₄ alkyl, hydroxy        and C₁-C₄ alkoxy; aralkyl; and C₅-C₇monocyclic heteroaryl ring        containing one to three heteroatoms chosen from O, S and N,        unsubstituted or optionally substituted by one to three        substituents independently selected from halogen, CF₃, C₁-C₄        alkyl, hydroxy and C₁-C₄ alkoxy;    -   Y is (CH₂)_(n) wherein n is 1 or 2;    -   R is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, aryl or        aryl-C₁-C₄ alkyl.

With the proviso that m can not be 0 when G is:

-   -   wherein Q′ is H and Q is O and X is (C═O)_(m).

The present invention includes within its scope all possible isomers,stereoisomers and optical isomers and their mixtures, and thebioprecursors or metabolites of the compounds of formula (I).

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(v)β₃ integrin and therefore in another embodiment the presentinvention relates to a method of selectively inhibiting or antagonizingthe α_(v)β₃ integrin. The invention further involves treating orinhibiting pathological conditions associated therewith such asosteoporosis, humoral hypercalcemia of malignancy, Paget's disease,tumor metastasis, solid tumor growth (neoplasia), angiogenesis,including tumor angiogenesis, retinopathy including macular degenerationand diabetic retinopathy, arthritis, including rheumatoid arthritis,periodontal disease, psoriasis, smooth muscle cell migration andrestenosis in a mammal in need of such treatment. Additionally, suchpharmaceutical agents are useful as antiviral agents, andantimicrobials.

As evidenced by the continuing research in integrin antagonists and bythe shortcomings of the compounds and methods of the art, there stillremains a need for small-molecule, non-peptidic selective α_(v)β₃ and/orα_(v)β₅ antagonist that displays decreased side-effects, and improvedpotency, pharmacodynamic, and pharmacokinetic properties, such as oralbioavailability and duration of action, over already describedcompounds. Such compounds would prove to be useful for the treatment,prevention, or suppression of various pathologies enumerated above thatare mediated by α_(v)β₃ and/or α_(v)β₅ receptor binding and celladhesion and activation.

The compounds of this invention include 1) α_(v)β₃ integrin antagonists;or 2) α_(v)β₅ integrin antagonists; or 3) mixed or dual α_(v)β₃/α_(v)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(v)β₃and/or α_(v)β₅receptors in a mammal in need of such treatment comprisingadministering a therapeutically effective amount of the compounds of thepresent invention and pharmaceutical compositions of the presentinvention. Administration of such compounds and compositions of thepresent invention inhibits angiogenesis, tumor metastasis, tumor growth,skeletal malignancy of breast cancer, osteoporosis, Paget's disease,humoral hypercalcemia of malignancy, retinopathy, macular degeneration,arthritis including rheumatoid, periodontal disease, smooth muscle cellmigration,

Including restenosis and artherosclerosis, and microbial or viraldiseases.

The compounds of the present invention can be used, alone or incombination with other therapeutic agents, in the treatment ormodulation of various conditions or disease states described above.

In order to prevent bleeding side effects associated with the inhibitionof α_(v)β₃, it would be beneficial to have a high selectivity ratio ofα_(v)β₃ and α_(v)β₅over α_(v)β₃. The compounds of the present inventioninclude selective antagonists of α_(v)β₃ over α_(v)β₃.

The present invention relates to a class of compounds represented byFormula I

-   -   or a pharmaceutically acceptable salt thereof, wherein

-   -   is a 4-8 membered monocyclic or a 7-12 membered bicyclic ring,        containing 1 to 5 heteroatoms, selected from the group        consisting of O, N or S; optionally saturated or unsaturated,        optionally substituted with one or more substituents selected        from the group consisting of alkyl, haloalkyl, aryl, heteroaryl,        halogen, alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy,        hydroxyalkyl, thioalkyl, amino, alkylamino, arylamino,        alkylsulfonamide, acyl, acylamino, alkylsullone, sulfonamide,        allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,        carboxamide, cyano, and —(CH₂)_(m)COR wherein m is 0-2 and R is        hydroxy, alkoxy, alkyl or amino; with the proviso that when Y⁴        in formula I is H, the ring A may not be an oxazole, with X-Y        containing side-chain connected at the carbon-2 as in

The ring A may further contain a carboxamide, sulfone, sulfonamide or anacyl group.

-   -   A¹ is a 5-9 membered monocyclic or 8-14 membered poly-cyclic        heterocycle of the formula

-   -   containing at least one nitrogen atom and optionally 1 to 4        heteroatoms or groups, selected from O, N, S, SO₂ or CO;        optionally saturated or unsaturated; optionally substituted by        one or more R^(k) selected from the group consisting of hydroxy,        alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino,        alkylamino, halogen, acylamino, sulfonamide and —COR wherein R        is hydroxy, alkoxy, alkyl or amino; or A¹ is

-   -   wherein Y¹ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl; aryl;        hydroxy; alkoxy; cyano; amido; alkylcarbonyl; arylcarbonyl;        alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl;        haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl;        acyloxymethoxycarbonyl;    -   R² taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keta, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester; or    -   R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated; or    -   R² taken together with R⁷ forms a 5 membered heteroaromatic ring        fused with an aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; aralkyl; amino;        alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl,        arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl;        haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl;        arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl;        bicycloalkyl; aryl; acyl; benzoyl; or    -   NR⁷ and R⁸ taken together form a 412 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S;    -   R⁵ is selected from the group consisting of H and alkyl; or    -   A¹ is

-   -   wherein Y² is selected from the group consisting of alkyl;        cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;    -   Z₁ is selected from the group consisting of CH₂, CH₂O, O, NH,        CO, S, SO, CH(OH) and SO₂;    -   Z₂ is a 1-5 carbon linker optionally containing one or more        heteroatom selected from the group consisting of O, S and N;    -   alternatively Z₁-Z₂ may further contain a carboxamide, sulfone,        sulfonamide, alkenyl, alkynyl, or acyl group;    -   wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionally        substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,        alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,        carboxyalkyl, halogen, haloalkyl or acylamino;    -   Additionally, Z₁-Z₂ may contain a 5- or 6-membered aryl or        heteroaryl ring optionally substituted with R^(c), wherein the        heteroaryl ring may contain 1-3 heteroatoms selected from the        group consisting of O, N and S; R^(c) is selected from the group        consisting of H, alkyl, haloalkyl, aryl, heteroaryl, halogen,        alkoxyalkyl, aminoalkyl, hydroxy, alkoxy, carboxamide, or cyano.    -   X is selected from the group consisting of —CHR^(e)—, —NR^(f)—,        —O—, —S—, —SO₂—, and —CO— wherein R^(c) is H, lower alkyl,        alkoxy, cycloalkyl, alkoxyalkyl, hydroxy, alkynyl, alkenyl,        haloalkyl, thioalkyl or aryl; wherein when R^(c) is hydroxy, the        hydroxy group can optionally form a lactone with the carboxylic        acid function of the chain; wherein R^(f) is selected from the        group consisting of H, alkyl, aryl, aralkyl, and haloalkyl;    -   Y is selected from the group consisting of (CH₂)_(p), —CHR^(g)—,        —NR^(g)—, CO and SO₂, wherein R^(g) is selected from the group        consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl, aryl,        heteroaryl, aralkyl, hydroxy, alkoxy, and carboxyalkyl; wherein        p is 0 or 1.

Optionally the group X-Y can contain a moiety selected from the groupconsisting of acyl, alkyl, sulfonyl, amino, ether, thioether,carboxamido, sulfonamido, aminosulfonyl and olefins;

-   -   Y³ and Y⁴ are independently selected from the group consisting        of H, alkyl, haloalkyl, halogen, aryl, aralkyl, heteroaryl,        heteroaryl, hydroxyalkyl, alkenes, and alkyne; wherein the alkyl        chain may be straight or branched and optionally containing one        or more heteroatoms selected from the group consisting of N, O,        and S, and may further contain a sulfone, sulfonamide, nitrile,        carboxamide, carboalkoxy or carboxyl group; wherein aryl and        heteroaryl rings may be monocyclic or bicyclic optionally        containing 1-5 heteroatoms and wherein said ring may be        saturated or unsaturated, and such rings may optionally be        substituted by one or more substituent selected front the group        consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen,        alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl,        thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl,        acylamino, alkylsulfone, sulfonamide, allyl, alkenyl,        methylenedioxy, ethylenedioxy, alkynyl, carboxamide, cyano, and        —(CH₂)_(m)COR wherein m is 0-2 and R is hydroxy, alkoxy, alkyl        or amino; with the proviso that when Y³ or Y⁴ is H, Y⁵ may be C        or N, otherwise Y⁵ is C; or    -   Y³ taken together with Y⁴ forms a 38 membered monocyclic or a        7-11 membered bicyclic ring B,

-   -   optionally containing one or more double bonds, optionally        containing one or more heteroatom or functional group selected        from O, NR⁸, S, CO or SO₂, optionally substituted with one or        more substituent selected from the group consisting of hydroxy,        halogen, haloalkyl, alkoxy, alkyne, cyano, alkylsulfone,        sulfonamide, carboalkoxy and carboxyalkyl; or    -   X taken together with Y³ forms a 3-7 membered monocyclic ring C,

-   -   optionally containing one or more double bonds, optionally        containing one or more heteroatom or functional group selected        from O, NR^(g), S, CO or SO₂, optionally substituted with one or        more substituent selected from the group consisting of alkyl,        halogen, alkoxy, haloalkyl, hydroxyalkyl, or alkoxyalkyl; and    -   R^(b) is X₂—R^(h) wherein X₂ is selected from the group        consisting of O, S and NR^(j) wherein R^(h) and R^(i) are        independently selected from the group consisting of H, alkyl,        aryl, aralkyl, acyl and alkoxyalkyl.

The compounds of the present invention comprise novel heteroarylalkanoicintegrin antagonists.

The present invention relates to the following compounds:

-   -   3-(3,5-ditert-butylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyr-        idin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid (TFA salt);    -   3-(3-tert-butyl-5-iodophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-napht-        hyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(3-tert-butyl-5-bromophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naph-        thyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(5-tert-Butyl-2-hydroxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-na-        phthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-[3,5-Ditert-butyl-2-(carboxymethoxy)phenyl]-4-{3-[3-(5,6,7,8-tetr-        ahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiaol-5-yl}butanoic        acid;    -   3-(5-tert-Butyl-2-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-na-        phthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(3,5-Ditert-butyl-4-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-{3-tert-Butyl-5-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)eth-        yl]-phenyl}-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,-4-oxadiazol-5-yl}butanoic        acid;    -   3-(3,4-Dicholophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(3-Fluoro-4-methylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthy-        ridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-(4-Phenoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2—yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(1-Benzofuran-2-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-[4-(Benzyloxy)phenyl]4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-[4-(Methylsulfonyl)phenyl]-4-[3-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-[4-(trifluoromethoxy)phenyl]butanoic acid        trifluoroacetate;    -   3-(3-Furyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)prop-        l]-1,2,4-oxadiazol-5-yl}butanoic acid trifluoroacetate;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-thien-3-ylbutanoic acid trifluoroacetate;    -   3-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,-8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-[3-(trifluoromethoxy)phenyl]butanoic acid        hydrochloride;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-(3,4,5-trifluorophenyl)butanoic acid        hydrochloride;    -   3-(2,2-Difluoro-1,3-benzodioxol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1-        ,8-naphthyridin-2-yl)propyl]1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-[3-Fluoro-5-(trifluoromethyl)phenyl]4-{3-[3-(5,6,7,8-tetrahydro-1-        ,8-naphthyridin-2-yl)proply]-1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-(6-Methoxy-2-naphthyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-(6-Methoxypyridin-3-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyri-        din-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(4-Cyanophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-Cyanophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-benzyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]—        1,2,4-oxadiazol-5-yl}butanoic acid trifluoroacetate;    -   3-(4-fluoro-3-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(3-Fluoro-5-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-(2-Methyl-1,3-benzothiazol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8—naphthyridin-2-yl)propyl]-1,2,-4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[2-(4-Chlorophenyl)-1,3-thiazol-5-yl]-4-{3-[3-(5,6,7,8-tetrahydro--1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[2-(4-Methoxyphenyl)-1,3-thiazol-5-yl]4-[3-[3-(5,6,7,8-tetrahydro--1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(2-Methyl-1,3-benzothiazol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8—naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[2-(4-Fluorophenyl)-1,3-thiazol-5-yl]4-{3-[3-(5,6,7,8-tetrahydro—        1,8-naphthyridin-2-yl)propyl]1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-[2-(3,5-Difluorophenyl)-1,3-thiazol-5-yl]-4-{3-[3-(5,6,7,8-tetrah-        ydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[2-(3,4-Difluorophenyl)-1,3-thiazol-5-yl]4-{3-[3-(5,6,7,8-tetrahy-        dro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[2-(2-Furyl)-1,3-thiazol-5-yl]4-{3-[3-(5,6,7,8-tetrahydro-1,8-nap-        hthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        hydrochloride;    -   3-(3,4-Dimethoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridi-        n-2-yl)propyl]1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(3,5-Dimethoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridi-        n-2-yl)propyl]1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(3,5-Dichlorophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(3,5-Difluorophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(3-Fluoro-4-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-[4-(trifluoromethyl)phenyl]butanoic acid        trifluoroacetate;    -   3-(2-Methyl-1,3-thiazol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-napht-        hyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(1-Phenyl-1H-pyrazol-4-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(1-Benzofuran-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin—        2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid hydrochloride;    -   3-(2,3-dihydro-1-benzofuran-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-n-aphthyridin-2-yl)propyl]1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(1,3-Benzodioxol-5-yl)-4-(3-{3-[(pyridin-2-ylamino)methyl]phenyl}--1,2,4-oxadiazol-5-yl)butanoic        acid hydrochloride;    -   3-(7-Fluoro-1,3-benzodioxol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-n-aphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(1,3-Benzoxazol-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridi-        n-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid hydrochloride;    -   3-(3-Methyl-1,2,4-oxadiazol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-n-aphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(3-Ethyl-1,2,4-oxadiazol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-na-        phthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   3-(3-Phenyl-1,2,4-oxadiazol-5-yl)-4-(3-[3-(5,6,7,8-tetrahydro-1,8-n-        aphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   [1-Benzoyl-4-({3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propy-1]-1,2,4-oxadiazol-5-yl}methyl)piperdin-4-yl]acetic        acid trifluoroacetate;    -   [1-Benzoyl-4-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-methyl)piperidin-4-yl]acetic        acid trifluoroacetate;    -   [1-(tert-Butoxycarbonyl)-4-({3-[3-(5,6,7,8-tetrahydro-1,8-naphthyri-        din-2-yl)propyl]-1,2,4-oxadiazol-5-yl]methyl)piperidin-4-yl]acetic        acid trifluoroacetate;    -   [1-(tert-Butoxycarbonyl)-4-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-o-xadiazol-5-yl{methyl)piperdin-4-yl]acetic        acid trifluoroacetate;    -   3-(4-Methylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(3-Chlorophenyl)-4-{-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(4-Methoxy-3-methylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphth-yridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-[4-(Methylthio)phenyl]-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-[4-(Methylthio)phenyl]-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-in-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(1-Methyl-1H-indol-3-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyr-idin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(1,1′-Biphenyl-4-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(3-Bromophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-(4-Bromophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(3-Phenoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthridin-2—yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid trifluoroacetate;    -   3-[3-Benzyloxy)phenyl]4{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin—2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(3-Bromo-4-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthy-        ridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid        trifluoroacetate;    -   4-{3-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxa-        diazol-5-yl}-3-(3,4,5-trimethoxyphenyl)butanoic acid        trifluoroacetate;    -   3-(2-Napthyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pr-        opyl]-1,2,4-oxadiazol-5-yl}butanoic acid hydrochloride;    -   3-(3-Nitrophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(3-Methylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(2-Fu        ryl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)prop-        yl]-1,2,4-oxadiazol-5-yl}butanoic acid hydrochloride;    -   3-(2-Methylphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]-        oxazin-6-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid, TFA;    -   4-{3-[3-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)propyl]-1,2,4--oxadiazol-5-yl}-3-(3,5-dimethoxyphenyl)butanoic        acid, TFA;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[3-(6,7,8,9-tetrahydro-5-oxa-1,9-diaza--benzocyclohepten-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-        butryic acid;    -   3-(3-Fluoro-4-methoxyphenyl)-4-{3-[3-(6,7,8,9-tetrahydro-5-oxa-1,9—        diaza-benzocyclohepten-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-(3,5-Difluorophenyl)-4-{3-[3-(6,7,8,9-tetrahydro-5-oxa-1,9-diaza—benzocyclohepten-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-(3,5-Dimethoxyphenyl)-4-{3-[3-(6,7,8,9-tetrahydro-5-oxa-1,9-diaza--benzocyclohepten-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butryic        acid;    -   3-(2-Methylbenzothiazol-5-yl)-4-{3-[3-(6,7,8,9-tetrahydro-5-oxa-1,9--diaza-benzocyclohepten-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-        butryic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[3-(1,2,3,5-tetrahydropyrido[2,3-e][1-,4]oxazepin-8-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid, TFA;    -   3-(3,5-dimethoxyphenyl)-4-{3-[3-(1,2,3,5-tetrahydropyrido[2,3-e][1,-4]oxazepin-8-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid, TFA;    -   3-(1,3-Benzodioxol-5-yl)-4-(3-{3-[6-(methylamino)pyridin-2-yl]propy-l}-1,2,4-oxadiazol-5-yl)butanoic        acid hydrochloride;    -   3-(3-Fluorophenyl)-4-(3-{3-[6-(methylamino)pyridin-2-yl]propyl}-1,2-        ,4-oxadiazol-5-yl)butanoic acid trifluoroacetate;    -   3-(1,3-benzodioxol-5-yl)-4-(3-3-[6-(ethylamino)pyridin-2-yl]propyl—        1,2,4-oxadiazol-5-yl)butanoic acid trifluoroacetate;    -   3-(3-Fuorophenyl)-4-(3-{3-[6-(methylamino)        pyridin-2-yl]propyl-1,2,-4-oxadiazol-5-yl)butanoic acid        trifluoroacetate;    -   3-(1,3-Benzodioxol-5-yl)-4-(3-{4-[(4-methylpyridin-2-yl)amino]butyl-        }-1,2,4-oxadiazol-5-yl)butanoic acid;    -   3-(1,3-benzodixoxol-5-yl)-4-(3-{4-[(6-methylpyridin-2-yl)amino]butyl-        }-1,2,4-oxadiazol-5-yl)butanoic acid;    -   (2-{6-[2-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)ethoxy]pyridin-3--yl}cyclopropyl)acetic        acid;    -   3-Methyl-4-{6-[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethoxy]p-        yridin-3-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)propyl]-1,3,4-oxadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(3-fluorophenyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,3,4-oxadiazol-2-yl}butanoic        acid trifluoroacetate;    -   3-(3-Fluoro-4-methoxyphenyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphth-        yridin-2-yl)propyl]-1,3,4-oxadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(3,5-Dimethoxyphenyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridi-        n-2-yl)propyl]-1,3,4-oxadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(2-Methyl-1,3-thiazol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-napht-        hyridin-2-yl)propyl]-1,3,4-oxadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(4-Fluorophenyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-y-l)propyl]-1,3,4-oxadiazol-2-yl}butanoic        acid trifluoroacetate;    -   3-(3,5-Difluoropehnyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]-1,3,4-oxadiazol-2-yl}butanoic        acid trifluoroacetate;    -   3-(3,5-Difluorophenyl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin--2-yl)propyl]1,3,4-thiadiazol-2-yl}butanoic        acid trifluoroacetate;    -   3-(4-Fluorophenyl)-4{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl-)propyl]-1,3,4-thiadiazol-2-yl}butanoic        acid trifluoroacetate;    -   3-(2-Methyl-1,3-thiazol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-napht-        hyridin-2-yl)propyl]-1,3,4-thiadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(1,3-Benzodioxol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)propyl]-1,3,4-thiadiazol-2-yl}butanoic acid        trifluoroacetate;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[2-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)ethoxy]isoxazol-5-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)propyl]-2H-tetraazol-2-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)propyl]-1H-tetraazol-1-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[2-(5,6,7,8-tetrahydro-1,8-naphthyrid-        in-2-yl)ethoxy]-1H-pyrazol-5-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[3-(4,5-dihydro-1H-imidazol-2-ylamino-)propoxy]isoxazol-5-yl}butanoic        acid;    -   3-[2-(4-chlorophenyl)-1,3-thiazol-5-yl]4-{3-[2-(5,6,7,8-tetrahydro—        1,8-naphthyridin-2-yl)ethoxy]isoxazol-5-yl}butanoic acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[2-(6,7,8,9-tetrahydro-5-oxa-1,9-diaza--benzocyclohepten-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-oxo-2-[2-(6,7,8,9-tetrahydro-5-oxa-1,9--diaza-benzocyclohepten-2-yl)-ethyl]-2,3-dihydro-isoxazol-5-        yl}-butyric acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]-        oxazin-6-yl)ethoxy]isoxazol-5-yl}butanoic acid, TFA;    -   3-(1,3-benzodioxol-5-yl)-4-{2-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]-oxazin-6-yl)ethyl]-3-oxo-2,3-dihydroisoxazol-5-        yl}butanoic acid, TFA;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[2-(1,2,3,5-tetrahydropyrido[2,3-e][1-,4]oxazepin-8-yl)ethoxy]isoxazol-5-yl}butanoic        acid, TFA;    -   3-(1,3-benzodioxol-5-yl)-4-{3-oxo-2-[2-(1,2,3,5-tetrahydropyrido[2,-3-e][1,4]oxazepin-8-yl)ethyl]-2,3-dihydroisoxazol-5-yl}butanoic        acid, TFA;    -   3-(1,3-benzodioxol-5-yl)-4-(3-{2-[5-(methoxymethyl)-6-(methylamino)-        pyridin-2-yl]ethoxy}isoxazol-5-yl)butanoic acid, TFA;    -   3-(1,3-Benzodioxol-5-yl)-4-{3-[3-(5,5-dimethyl-5,6,7,8-tetrahydro-1-        ,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl-4-{3-[3-(1-methyl-1,2,3,4-tetrahydropyrido-        [2,3-b]pyrazin-6-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic acid;    -   3-(2-methyl-1,3-benzothizol-5-yl)-4-{3-[3-(1-methyl-1,2,3,4-tetrah-ydropyrido[2,3-b]pyrazin-6-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-fluoro-4-methoxyphenyl)-4-{3-[3-(1-methyl-1,2,3,4-tetrahydropy-        rido[2,3-b]pyrazin-6-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(6-methoxypyridin-3-yl)-4-{3-[3-(1-methyl-1,2,3,4-tetrahydropyrid-o[2,3-b]pyrazin-6-yl)propyl]-1,2,4-oxydiazol-5-yl}butanoic        acid;    -   3-(1,3-benzodioxol-5-yl)-4-(3-{[2-(5,6,7,8-tetrahydro-1,8-naphthyri-        din-2-yl)ethyl]thio}-1H-1,2,4-triazol-5-yl)butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-(1-methyl-5-{[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]thio}-1H-1,2,4-triazol-3-yl)butanoic        acid;    -   3-(1,3-benzodioxol-5-yl)-4-(4-methyl-5-{[2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl]thio}4H-1,2,4-triazol-3-yl)butanoic        acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[2-(1-methyl-1,2,3,4-tetrahydropyrido-        [2,3-b]pyrazin-6-yl)ethoxy]isoxazol-5-yl}butanoic acid;    -   3-(1,3-benzodioxol-5-yl)-4-(3-{2-[6-(methylamino)pyridine-2-yl]ethox-y}isoxazol-5-yl)butanoic        acid; and    -   3-(6-methoxypyridin-3-yl)-4-{3-[2-(5,6,7,8-tetrahydro-1,8-naphthyri-        din-2-yl)ethoxy]isoxazol-5-yl}butanoic acid.

In another embodiment, the present invention may also include thefollowing compounds:

-   -   3-methyl-4-(3-{3-[(pyridin-2-ylamino)methyl]phenyl}-1,2,4-oxadiazol--5-yl)butanoic        acid;    -   3-methyl-4-(3-{4-[(pyridin-2-ylamino)methyl]phenyl}-1,2,4-oxadiazol--5-yl)butanoic        acid;    -   3,3-dimethyl-4-{4-[4-(pyridin-2-ylamino)butyl]-1,3-thiazol-2-yl}butanoic        acid;    -   [1-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}methyl)cyclo-pentyl]-acetic        acid;    -   4-phenyl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-butanoic        acid;    -   2-phenyl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-butanoic        acid;    -   3,3-dimethyl-4-{3-[2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl]1,2,4-oxadiazol-5-yl}butanoic        acid;    -   [1-({3-[2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl--1,2,4-oxadiazol-5-yl}methyl)cyclopentyl]acetic        acid;    -   4-{3-[2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl]-1-,2,4-oxadiazol-5-yl}4-phenylbutanoic        acid;    -   4-{3-[2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl]-1-,2,4-oxadiazol-5-yl}2-phenylbutanoic        acid;    -   4-{3-[2-(2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl]-1-,2,4-oxadiazol-5-yl}4-phenylbutanoic        acid;    -   3,3-dimethyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   [1-({3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}methyl)cyclopentyl]acetic        acid;    -   4-phenyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   2-phenyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(1,3-benzodioxol-5-yl)-4-{3-[4(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-quinolin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-quinolin-3-yl-4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5--yl}-butanoic        acid;    -   3-(3-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-methoxyphenyl)-4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-methoxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-methoxyphenyl)-4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-fluorophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-fluorophenyl)-4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-1-5-yl}butanoic        acid;    -   3-(4-fluorophenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(4-fluorophenyl)-4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-1-5-yl}butanoic        acid;    -   4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}-3-[3-(trifluoromethyl)phenyl]butanoic        acid;    -   4-{3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-3-[3-(trifluoro-methyl)-phenyl]butanoic        acid;    -   3-(3-hydroxyphenyl)-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-(3-hydroxyphenyl)-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-pyridin-3-yl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-butanoic        acid;    -   3-phenyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-propyl]--1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-phenyl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-methyl-3-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-methyl)pentanoic        acid;    -   [1-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}methyl-cyclohexyl]acetic        acid;    -   3-methyl-3-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}-methyl)-hexanoic        acid;    -   3,4-dimethyl-3-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}methyl)-pentanoic        acid;    -   3-ethyl-3-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}methyl)-pentanoic        acid;    -   4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-methyl-3-phenyl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol--5-yl}butanoic        acid;    -   3-Methyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl-]-[1,2,4]oxadiazol-5-ylmethyl}-pentanoic        acid;    -   3-Methyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl-]-[1,2,4]oxadiazol-5-ylmethyl}-hexanoic        acid;    -   3,4-Dimethyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-ylmethyl}-pentanoic        acid;    -   3-Ethyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]--[1,2,4]oxadiazol-5-ylmethyl}-pentanoic        acid;    -   3-Methyl-3-phenyl-4-(3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-Phenyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl-]-[1,2,4]oxadiazol-5-ylmethyl}-pentanoic        acid;    -   3-Phenyl-3-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl-]-[1,2,4]oxadiazol-5-ylmethyl}-hexanoic        acid;    -   4-{3-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,2,4]-oxa-diazol-5-yl)-butyric        acid;    -   3-Methyl-3-pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   (1-Acetyl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-ylmethyl}-piperidin-4-yl)-acetic        acid;    -   1-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-ylmethyl}-cyclohexyl)-acetic        acid;    -   3-Methyl-3-pyridin-3-yl-4-{3-[4-(pyridin-2-ylamino)butyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   4-(benzyloxy)-3-({3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}methyl)-butanoic        acid;    -   4-[4-(N-pyridin-2-yl-beta-alanyl)piperazin-1-yl]butanoic acid;    -   4-{4-[3-(pyridin-2-ylamino)propyl]piperazin-1-yl}butanoic acid;    -   2-methyl-6-[3(2-pyridylamino)propoxy)-3-pyridinebutanoic acid;    -   β,β-dimethyl-3-[5-(2-pyridinylamino)pentyl]-1,2,4-oxadiazole-5-butanoic        acid;    -   β,β-dimethyl-3-[4-(2-pyridinylamino)butyl]-1,2,4-oxadiazole-5-butanoic        acid;    -   β,β-dimethyl-3-[[[2-(2-pyridinylamino)ethyl]thio]methyl-1,2,4-oxadiazole-5-butanoic        acid;    -   4-Carboxymethyl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)--propyl]-[1,2,4]oxadiazol-5-ylmethyl}-piperidine-1-carboxylic        acid tert-butyl ester;    -   (1-Benzoyl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,2,4]oxadiazol-5-ylmethyl}-piperidin-4-yl)-acetic        acid;    -   [4-{3-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,2,4-]oxadiazol-5-ylmethyl}-1-(2,2,2-trifluoroacetyl)piperidine-4-yl]-acetic        acid;    -   4-(phenylthio)3-({3-[4-(pyridine-2-ylamino)butyl]-1,2,4-oxadiazol-5--yl}methyl)butanoic        acid;    -   4-(phenylthio)3-({3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}methyl)butanoic        acid;    -   3-methyl-4-{3-[4-(pyridin-2-ylamino)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid hydrochloride;    -   3-methyl-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   ((1S,2R)-2-(3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}cyclepropyl)acetic        acid;    -   ((1S,2S)-2-(3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]-1,2,4-oxadiazol-5-yl}cyclepropyl)acetic        acid;    -   3-Pyridin-3-yl-4-{5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)--        propyl]4H-[1,2,4]triazol-3-yl}butyric acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-tetrazol-2-yl}-butyric        acid;    -   (2-{5-[3-(5,6,7,8-Tetrahydro-1,8-naphthyridin-2-yl)-propyl]-[1,3,4]oxa-diazol-2-yl}-cyclopropyl)-acetic        acid;    -   3-Phenyl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-[1,3,4]oxadiazol-2-yl)butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,3,4]oxadiazol-2-yl}butyric        acid;    -   3-(3-Fluoro-phenyl)-4-(5-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2--yl)-        propyl]-[1,3,4]oxadiazol-2-yl}-butyric acid;    -   3-Benzo-[1,3]dioxol-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-        propyl]-[1,3,4]oxadiazol-2-yl}butyric acid;    -   (2-(2-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-cyclopropyl)acetic        acid;    -   3-Phenyl-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-2H-tetrazol-5-yl}butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-2H-tetrazol-5-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-2H-tetrazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-(2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-(2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   (2-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-3-yl}-cyclopropyl)-acetic        acid;    -   3-Phenyl-4-(5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-isoxazol-3-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-(5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-3-yl-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-(5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-        propyl]-isoxazol-3-yl}-butyric acid;    -   3-Pyridin-3-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-3-yl}butyric        acid;    -   3-Benzo[1,3]dioxyl-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-        propyl]-isoxazol-3-yl}-butyric acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-(3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-5-yl-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-isoxazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-5-yl}butyric        acid;    -   3-Benzo-[1,3]dioxol-5-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-        propyl]-isoxazol-5-yl}-butyric acid;    -   3-Phenyl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-1H-pyrazol-3-yl}butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-1H-pyrazol-3-yl-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl        propyl]-1H-pyrazol-3-yl}-butyric acid;    -   3-Pyridin-3-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-1H-pyrazol-3-yl}butyric        acid;    -   3-Benzo-[1,3]dioxol-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-        propyl]-1H-pyrazol-3-yl}-butyric acid;    -   (2-{3-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-5-yl}-cyclopropyl)-acetic        acid;    -   (2-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-1H-pyrazol-3-yl}-cyclopropyl)-acetic        acid;    -   (2-{4-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazo-1-2-yl}-cyclopropyl)-acetic        acid;        3-Phenyl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazol-2-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl-thiazol-2-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl)-thiazol-2-yl)-butyric        acid;    -   3-Pyridin-3-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazol-2-yl}butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazol-2-yl}-butyric        acid;    -   3-Phenyl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-        }-pyrazol-1-yl}-butyric acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyrid-in-2-yl)-propyl]-pyrazol-1-yl)-butyric        acid;    -   3-Phenyl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl-]-imidazol-1-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid3-Phenyl-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-Benzol[1,3]dioxol-5-yl-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyrid-in-2-yl)-ethoxy]-isoxazol-5-yl)-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-Phenyl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy-]-2H-pyrazol-3-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-2H-pyrazol-3-yl)-butyric        acid;    -   3-Phenyl-4-[4-(2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propiony-1)-imidazol-1-yl]-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-[4-(3-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl-propionyl        imidazole-1-yl]-butyric acid;    -   3-(3-Fluoro-phenyl)-4-[4-(3-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl-propionyl)-imidzol-1-yl]-butyric        acid;    -   3-Pyridin-3-yl-4-[4-(3-5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl-propionyl)-imidazol-1-yl]-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-[4-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-imidazol-1-yl]-butyric        acid;    -   4-{4-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[1-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[1-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl]-propyl]-imidzol-1-yl}-butyric        acid;    -   4-{4-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   4-{4-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   4-{4-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-(3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-prop-1-ynyl]-imidzol-1-yl]-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{2-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-2H-tetrazol-5-yl}-butyric        acid;    -   (2-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-3-yl}-cyclopropyl)-acetic        acid;    -   3-Phenyl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-isoxazol-3-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-3-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-isoxazol-3-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-3-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-3-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-(3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2--yl)-propyl]-isoxazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-isoxazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-isoxazol-5-yl}-butryic        acid;    -   3-Phenyl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-]-1H-pyrazol-3-yl}-butryic        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-1H-pyrazol-3-yl≢-butryic        acid;    -   3-(3-Fluoro-phenyl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-propyl]-1H-pyrazol-3-yl}-butryic        acid;    -   3-Pyridin-3-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propyl]-1H-pyrazol-3-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-1H-pyrazol-3-yl}-butryic        acid;    -   (2-{3-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl}-propyl]-isoxazol-5-yl}-cyclopropyl)-acetic        acid;    -   2-{5-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl}-propyl]-1H-pyrazol-3-yl}-cyclopropyl)-acetic        acid;    -   2-{4-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl}-propyl]-thiazo-1-2-yl}-cyclopropyl)-acetic        acid;    -   3-Phenyl-4-{-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]--thiazol-2-yl}butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazol-2-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-        yl)-propyl]-thiazol-2-yl}-butyric acid;    -   3-Pyridin-3-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propyl]-thiazol-2-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-thiazol-2-yl}-butyric        acid;    -   3-Phenyl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-        ]-pyrazol-1-yl}-butryic acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-≡3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-propyl]-pyrazol-1-yl≢-butryic        acid;    -   3-Pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Phenyl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl-        ]-imidazol-1-yl}-butryic acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{4-ο3-(5,6,7,8-tetrahydro-[1,8]naphthryidin-2-yl)—propyl]-imidazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butryic        acid3-Phenyl-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}butryic        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{3-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-]2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-isoxazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-Phenyl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy-        ]-2H-pyrazol-3-yl}-butyric acid;    -   3-Pyridin-3-yl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—ethoxy]-2H-pyrazol-3-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{5-[2-(5,6,7,8-tetrahydro-[1,8]naphthryidin-2-yl)-ethoxy]-2H-pyrazol-3-yl}-butryic        acid;    -   3-Phenyl-4-[4-(3-5,6,7,8-tetrahydro-[1,8]naphthryidin-2-yl-propionyl)-imidazol-1-yl]-butryic        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-[4-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-imidazol-1-yl]-        butryic acid;    -   3-(3-Fluoro-phenyl)-4-[4-(3-5,6,7,8-tetrahydro-[1,8]naphthryidin-2—yl-propionyl)-imidazol-1-yl]-butryic        acid;    -   3-Pyridin-3-yl-4-[4-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-imidazol-1-yl]-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-]4-(3-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl-propionyl)-imidazol-1-yl]butryic        acid;    -   4-{4-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-imidazol-1-yl}-3-phenyl-butryic        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[1-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butryic        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[1-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-imidazol-1-yl}butryic        acid;    -   4-{5-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl        propyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric acid;    -   4-{5-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   4-{5-[1-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propylynyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-imidazaol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-prop-1-ynyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-pyrazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-pyrazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-pyrazol-1-yl}butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]-pyrazol-1-yl}-3-pyridin-3-yl-butyric        acid3-Benzo[1,3]dioxol-5-yl-4--{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-prop-1-ynyl]—pyrazol-1-yl}butyric        acid4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-pyrazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)-propenyl]-pyrazol-1-yl}-butyric        acid3-(3-Fluoro-phenyl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-pyrazol-1-yl≢-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propenyl]-pyrazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propenyl]-pyrazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propenyl]-pyrazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-3-pyridin-3-yl-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl]-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-imidazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-3-phenyl-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-(4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-butyric        acid;    -   4-{4-[3-Hydroxy-3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)-propyl]-pyrazol-1-yl}-3-pyridin-3-yl-butryic        acid;    -   3-(3-Fluoro-phenyl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2--yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   3-Phenyl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   3-(2,3-Dihydro-benzofuran-6-yl)-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propenyl]-imidazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-imidazol-1-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propenyl]-pyrazol-1-yl}-butyric        acid;    -   3-Pyridin-3-yl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)—propenyl]-pyrazol-1-yl}-butyric        acid;    -   3-Phenyl-4-{4-[3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propenyl]-pyrazol-1-yl}-butyric        acid;    -   3-hydroxy-4-{3-[4-(pyridine-2-ylamio)butyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-hydroxy-4-{3-[3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propyl]--1,2,4-oxadiazol-5-yl}butanoic        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[4-(1H-imidazol-3-ylamino)-butyl]-[1,2-,4]oxadiazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[4-(1H-imidazol-2-ylamino)-butyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[4-(2H-pyrazol-3-ylamino)-butyl]-1,2,-4]oxadiazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[4-(2H-pyrazol-3-ylamino)-butyl]-[1,2,4]oxadiazol-5-yl}-buutyric        acid;    -   3-Benzo]1,3]dioxol-5-yl-4-{3-[4-(3H-imidazol-4-ylamino)-butyl]-[1,2-,4]oxadiazol-5-yl≢-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[4-(3H-imidazol-4-ylamino)-butyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-Benzo[1,3]dioxol-5-yl-4-{3-[3-(6-methylamino-pyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[3-(6-methylamino-pyridin-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   4-{3-[3-(6-Ethylamino-pyridin-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl≢—3-(3-fluoro-phenyl)-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-(3-{3-[6-(2-methoxy-ethylamino)-pyridin-2-yl]--propyl}-[1,2,4]oxadiazol-5-yl)-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-(3-{3-[6-(3-methoxy-propylamino)-pyridin-2-yl-        ]-propyl}-[1,2,4]oxadiazol-5-yl)butyric acid;    -   3-(3-Fluoro-phenyl)-4-(3-{3-[6-(2,2,2-trifluoro-ethylamino)-pyridin--2-yl]-propyl}-[1,2,4]oxadiazol-5-yl)-butyric        acid;    -   3-(3-Fluoro-phenyl)-4-{3-[3-(5-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-propyl]-[1,2,4]oxadiazol-5-yl}-butyric        acid;    -   4-{3-[3-(5,5-Dimethyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-yl}-3-(3-fluoro-phenyl)-butyric        acid;    -   4-{3-[3-(5,5-Difluoro-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)propyl]-[1,2,4]oxadiazol-5-yl}-3-(3-fluoro-phenyl)butyric        acid; and    -   3-(1,3-benzodioxol-5-yl)-4-{3-{(5,6,7,8-tetrahydro-1,8-naphthyridin--2-ylmethoxy)methyl]-1,2,4-oxadiazol-5-yl}butanoic        acid;

In another embodiment of the present invention

-   -   is a heteroaryl substituted by one or more substituents selected        from lower alkyl, alknyl, alkenyl, halogen, alkoxy, hydroxy,        cyano, amino, alkylamino, dialkylamino or methylsulfonamide.        More specifically, some examples of heteroaryl include        oxadiazole, pyrimidine, imidazole, thiadiazole, triazole,        tetrazole, pyrazole, isoxazole, and thiazole.

Other embodiments of

-   -   include the following heterocyclic ring systems containing at        least one nitrogen atom:

-   -   wherein Z_(n) is H, alkyl, alkoxy, hydroxy, amine, alkylamine,        dialkylamine, carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or        haloalkyl and R¹ is H, alkyl, alkoxyalkyl, acyl, haloalkyl or        alkoxycarbonyl. More specifically some examples include        pyridylamino, imidazolylamin, morpholinopyridine,        tetrahydronaphthyridine, oxazolylamino, thiazolylamino,        pyrimidinylamino, quinoline, tetrahydroquinoline,        imidazopyridine, benzimidazole, pyridone or quinolone.

The following heteroaryls include the ring systems described above.

RECTIFIED SHEET (RULE 91)

RECTIFIED SHEET (RULE 91)

For the pyridyl derived heterocycle, the substituents X₄ and X₅ areselected from the group consisting of H, alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano or acylamino groups.

In another embodiment of the invention, the substituents X₄ and X₅ canbe methyl, methoxy, amine, methylamine, trifluoromethyl, dimethylamine,hydroxy, chloro, bromo, fluoro and cyano. X₆ may preferentially be H,alkyl hydroxy, halogen, alkoxy and haloalkyl. Alternately, the pyridylring can be fused with a 4-8 membered ring, optionally saturated orunsaturated. Some examples of these ring systems includetetrahydronaphthyridine, quinoline, tetrahydroquinoline, azaquinoline,morpholinopyridine, imidazopyridine and the like. The monocyclic ringsystems such as imidazole, thiazole, oxazole, pyrazole, and the like,may contain an amino or alkylamino substituent at any position withinthe ring.

In another embodiment of the present invention, when Z₁ of Formula I isCO or SO₂, the linkage A¹-Z₂ of Formula I includes the heterocyclederived ring systems such as: pyridine, imidazole, thiazole, oxazole,benzimidazole, imidazopyrdine and the like.

Other heterocycles for A¹-Z₂ of the present invention include

-   -   wherein X₄ is as defined above.

In another embodiment, Y³ or Y⁴ is an aryl or a heteroaryl groupselected from phenyl, benzofuran, benzothiophene, indole, quinoline,isoquinoline, benzimidazole, benzoxazole, 1,3-benzodioxole,1,4-benzodioxane, benzopyran, quinolone, imidazopyridine,tetrahydro-quinoline, benzotriazole, dihydroindole, dihydrobenzofuran,furan, thiophene, phenyl, oxazole, thiazole, isoxazole, pyrazole,imidazole, pyrrole, pyridine, pyrimidine, pyridone, triazole,thiadiazole and the like. The aryl system can be optionally substitutedat one or more positions with alkyl, alkoxy, hydroxy, cyano, halogen orhaloalkyl.

In another embodiment of the present invention, Y³ or Y⁴ may be anamine, alkylamine, acylamine, aminosulfone (NHSO₂R), arylamine,alkoxyalkylamine, aralkylamine, or heterocyclic amine.

In another embodiment of the present invention, Y³ taken together withY⁴ forms a 3-8 membered monocyclic or 7-11 membered bicyclic ring B,

-   -   optionally containing one or more double bonds, optionally        containing one or more heteroatoms or functional groups selected        from O, NR⁸, S, CO or SO₂, optionally substituted with one or        more substituent selected from the group consisting of alkyl,        haloalkyl, halogen, haloalkyl, alkoxy, alkyne, cyano,        alkylsulfone, sulfonamide, carboalkoxy and carboxyalkyl; wherein        R^(g) is selected from the group consisting of alkyl, haloalkyl,        alkoxyalkyl, aryl, heteroaryl, aralkyl and carboxyalkyl.

In another embodiment of the present invention, X taken together with Y³forms a 3-7 membered monocyclic ring C,

-   -   optionally containing one or more double bonds, optionally        containing one or more heteroatom or functional group selected        from O, NR⁸, S, CO or SO₂, optionally substituted with one or        more substituent selected from the group consisting of alkyl,        halogen, alkoxy, haloalkyl, hydroxyalkyl, or alkoxyalkyl;        wherein R^(g) is selected from the group consisting of H, alkyl,        haloalkyl, alkoxyalkyl, aryl, heteroaryl, aralkyl, and        carboxyalkyl.

The invention further relates to pharmaceutical compositions containingtherapeutically effective amounts of the compounds of Formula I.

The present invention as a first object provides novel non-peptidecompounds having the following formula (I)

-   -   wherein:    -   G is a group selected among:

-   -   wherein Q is NH or O and Q′ is H C1-C6 alkyl, phenyl, or        phenyl-C1-C4-alkyl;

-   -   X is a direct linkage, CH₂—CONH, —(CH₂)_(m)— or (CH₂)_(m)—X′        wherein X′ is O, S or NH and m is an integer of 1 to 4;    -   B is CONH, CH₂—CONH, —(CH₂)_(m)— or C₂-C₄ alkylene or C₂-C₄        alkenylene chain or —(CH₂)_(m)—X′, wherein X′ and m are as        defined above;    -   A is a phenyl or pyridine ring, unsubstituted or optionally        substituted by one to to three substituents chosen independently        from halogen, CF₃, C₁-C₄ alkyl, OH and C₁-C₄ alkoxy;    -   Y is selected from O or S(O)_(n) wherein n is zero, 1 or 2;    -   R is C₁-C₆ alkyl or a phenyl or C₅-C₇ monocyclic heteroaryl ring        containing one to three heteroatoms chosen from O, S, and N        unsubstituted or optionally substituted by one to three        substituents chosen independently from halogen, CF₃, C₁-C₄        alkyl, hydroxy and C₁-C₄ alkoxy;    -   R′ is hydrogen, C₁ -C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl        or aryl-C₁-C-₄ alkyl;    -   and the pharmaceutically acceptable salts thereof.

The present invention includes within its scope all possible isomers,stereoisomers and optical isomers and their mixtures, and themetabolites and the metabolic precursors or bioprecursors of thecompounds of formula (I).

A halogen atom is preferably chlorine or fluorine.

The alkyl, alkoxy, alkenyl and alkynyl groups and the alkylene andalkenylene chains may be branched or straight groups or chains,respectively.

A C₅-C₇ monocyclic heteroaryl ring is preferably a C₅-C₆heteromonocyclic ring, in particular selected from pyridine, pyrazine,pyridazine, pyrimidine, thiophene, pyrrole, pyrazole, imidazole, oxazoleand isoxazole.

An aryl group is e.g., an aromatic C₆-C₂₀ mono- or poly-nuclear moiety,typically phenyl, unsubstituted or substituted by one to threesubstituents independently chosen from halogen, hydroxy, CF₃, C₁-C₄alkyl and C₁-C₄ alkoxy.

Accordingly an aralkyl group is e.g. benzyl or phenethyl, in which thephenyl ring is optionally substituted by one to three substituentsindependently chosen from halogen, hydroxy, CF₃, C₁-C₄alkyl and C₁-C₄alkoxy.

A C₂-C₄ alkenyl group is preferably an allyl group.

A C₁-C₆ alkyl group is preferably as C₁-C₄ alkyl group.

A C₁-C₄ alkyl group is preferably a methyl or ethyl group.

A C₂-C₄ alkynyl group is preferably an ethynyl group.

A C₂-C₄ alkoxy group is preferably methoxy, ethoxy, propoxy and butoxy.

Examples of pharmaceutically acceptable salts of the compounds of theinvention are either those with inorganic bases, such as sodium,potassium, calcium and aluminium hydroxides, or with organic bases, suchas lysine, arginine, N-methyl-glucamine, triethylamine, triethanolamine,dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine,N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine,β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamineand the other acceptable organic amines, as well as the salts withinorganic acids, e.g. hydrochloric, hydrobromic and sulphuric acids andwith organic acids, e.g. citric, tartaric, maleic, malic, fumaric,trifluoroacetic, methanesulphonic and ethanesulphonic acids. As statedabove the present invention also includes within its scopepharmaceutically acceptable bio-precursors (otherwise known aspro-drugs) of the compounds of formula (I), i.e. compounds which have adifferent formula to formula (I) above, but which nevertheless uponadministration to a human being are converted directly or indirectly invivo into a compound of formula (I).

Preferred compounds of the invention are those wherein, in formula (I),

-   -   G is as defined above;    -   X is a direct linkage or (CH₂)_(m)—X′, in which m is 1 or 2 and        X′ is as defined above;    -   B is CONH or CH═CH or CH₂—X′, wherein X is as defined above;    -   A is a phenyl ring unsubstituted or optionally substituted by        one or two substituents selected from halogen CF₃, C₁-C₄ alkyl,        OH, and C₁-C4 alkoxy;    -   Y is as defined above;    -   R is a phenyl, pyridine, pyrazine, pyridazine, pyrimidine,        thiophene, pyrrole, pyrazole, imidazole, oxazole or isoxazole        ring, unsubstituded or optionally substituted by one or two        substituents selected from halogen, CF₃, C₁-C₄ alkyl, OH and        C₁-C₄ alkoxy;    -   R′ is hydrogen, C₁-C₆ alkyl; and the pharmaceutically acceptable        salts thereof.

A further class of preferred compounds of the invention are thosewherein, in formula (I),

-   -   G and Y are as defined above;    -   X is CH2-CONH or (CH₂)_(m)—X′, in which m and X′ are as defined        above;    -   A is a phenyl or pyridine ring, unsubstituted or optionally        substituted by one to three substituents chosen independently        from halogen, CF₃, C₁-C₄ alkyl, OH and C₁-C₄ alkoxy;    -   B is CONH or CH₂—CONH;    -   R is a phenyl, pyridine, pyrazine, pyridazine, pyrimidine,        thiophene, pyrrole, pyrazole, imidazole oxazole or isoxazole        ring, unsubstituded or optionally substituted by one or two        substituents selected from halogen, CF₃, C₁-C₄ alkyl, OH and        C₁-C₄ alkoxy;    -   R′ is hydrogen, C₁-C₆ alkyl; and the pharmaceutically acceptable        salts thereof.

Most preferred compounds of the invention are those wherein, in formula(I),

-   -   G and Y are as defined above;    -   X is a direct linkage or (CH₂)_(m)—X′, in which m is 1 or 2 and        X′ is as defined above;    -   B is CONH or CH═CH or CH₂—X′, where X′ is as defined above;    -   A is a phenyl ring unsubstituted or optionally substituted by        one or two substituents selected from halogen, CF₃, C₁-C₄ alkyl,        OH and C₁-C₄ alkoxy;    -   R is a phenyl or pyridinehding, unsubstituded or optionally        substituted by one or two substituents selected from halogen,        CF₃, C₁-C₄ alkyl, OH and C₁-C₄alkoxy;    -   R′ is hydrogen, C₁-C₆ alkyl; and the pharmaceutically acceptable        salts thereof. Examples of specific preferred compounds        according to the invention are the following:    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino[phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3-pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3-pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3pyridinyl)propanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3pyridinyl)propanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3pyridinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl)sulfanyl-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl)sulfanyl-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl)sulfanyl-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-        imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-        imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-{2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-(3-pyridinyl)propanoic        acid    -   3-[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(4-{[(benzylamino)carbonyl]amino)benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{3-[(4-{[(benzylamino)carbonyl]amino)benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{4-[(4-{[(benzylamino)carbonyl]amino)benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(3-{[(benzylamino)(imino)methyl]aminobenzoyl)amino]phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(3-{[(benzylamino)(imino)methyl]aminobenzoyl)amino]phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(3-{[(benzylamino)(imino)methyl]aminobenzoyl)amino]phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy)-3-phenyl-propanoic        acid;    -   3-{3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy)-3-phenyl-propanoic        acid;    -   3-{4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy)-3-phenyl-propanoic        acid;    -   3-{2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-        phenylpropanoic acid;    -   3-[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-phenylpropanoic        acid;    -   3-[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-phenylpropanoic        acid;    -   3-[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxyl]-3-phenylpropanoic        acid;    -   3-{2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy-3-phenylpropanoic        acid;    -   3-{3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy-3-phenylpropanoic        acid;    -   3-{4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy-3-phenylpropanoic        acid;    -   3-(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-        phenylpropanoic acid;    -   3-(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-        phenylpropanoic acid;    -   3-(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-phenyl-3-(2-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-        phenylpropanoic acid;    -   3-{3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-        phenylpropanoic acid;    -   3-{4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-        phenylpropanoic acid;    -   3-[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-{2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-        phenylpropanoic acid;    -   3-(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-        phenylpropanoic acid;    -   3-(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-        phenylpropanoic acid;    -   3-(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-phenyl-3-(2-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(-3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-({2-[4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-a(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfon-        yl)-3-(3-pyridinyl)propanoic acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfon-        yl)-3-(3-pyridinyl)propanoic acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--        pyridinyl)propanoic acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino)phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino)phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino)phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-        pyridinyl)propanoic acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-        pyridinyl)propanoic acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-        pyridinyl)propanoic acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfin-        yl)-3-phenylpropanoic acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfin-        yl)-3-phenylpropanoic acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfin-        yl)-3-phenylpropanoic acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfon-        yl)-3-phenylpropanoic acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfon-        yl)-3-phenylpropanoic acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfon-        yl)-3-phenylpropanoic acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}sulfonyl]-propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   either as a single isomer or as a mixture thereof, or a        pharmaceutically acceptable salt thereof, in particular the        hydrochloride or the trifluoroacetate.

A further object of the present invention is to provide a compound orformula (I)

-   -   wherein:    -   G is a group selected among:

-   -   wherein Q is NH or O and Q′ is H, C1-C₆ alkyl, phenyl, or        phenyl-C1-C4-alkyl;

-   -   X is a direct linkage, CH₂—CONH, —(CH₂)_(m)—X′ wherein X′ is O,        S, or NH and m is an integer of 1 to 4;    -   B is CONH, CH₂—CONH, a C₂-C₄ alkylene or C₂-C₄ alkenylene chain        or —(CH₂)_(m)—X′, wherein X′ and m are as defined above;    -   A is a phenyl or pyridine ring, unsubstituted or optionally        substituted by one to three substituents chosen independently        from halogen, CF₃, C₁-C₄ alkyl, OH and C₁-C₄ alkoxy;    -   Y is selected from O or S(O)_(n) wherein n is zero, 1 or 2;    -   R is C₁-C₆ alkyl or a phenyl or C₅-C₇ monocyclic heteroaryl ring        containing one to three heteroatoms chosen from O, S, and N,        unsubstituted or optionally substituted by one to three        substituents chosen independently from halogen, CF₃, C₁-C₄        alkyl, hydroxy and C₁-C₄ alkoxy;    -   R′ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl        or aryl-C₁-C₄ alkyl;    -   or a pharmaceutically acceptable salt thereof, for use in a        method of treatment of the human or animal body by therapy, in        particular for treating conditions mediated by the αvβ3        integrin.

Object of the present invention is also to provide a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and/ordiluent and as an active principle, a compound of formula (I), as hereindefined, or a pharmaceutically acceptable salt thereof.

The present invention also provides the use of a compound of formula(I), a defined above, in the preparation of a medicament having αvβ3integrin inhibiting or antagonizing activity.

The present invention also provides a method for treating conditionsmediated by the αvβ3 integrin in a mammal, including humans, in need ofsuch treatment comprising administering to said mammal an effective αvβ3inhibiting or antagonizing amount of a compound of formula (I)

-   -   wherein:    -   G is a group selected among:

-   -   wherein Q is NH or O and Q′ is H, C1-C6 alkyl, phenyl, or        phenyl-C1-C4-alkyl;

-   -   X is a direct linkage, CH₂—CONH, —(CH₂)_(m)— or (CH₂)_(m)—X′        wherein X′ is O, S or NH and m is an integer of 1 to 4;    -   B is CONH, CH₂—CONH, a C₂-C₄ alkylene or C₂-C₄ alkenylene chain        or —(CH₂)_(m)—X′, wherein X′ and m are as defined above;    -   A is a phenyl or pyridine ring, unsubstituted or optionally        substituted by one to three substituents chosen independently        from halogen, CF₃, C₁-C₄ alkyl, OH and C₁-C₄ alkoxy;    -   Y is selected from O or S(O)_(n) wherein n is zero, 1 or 2;    -   R is C₁-C₆ alkyl or a phenyl or C₅-C₇ monocyclic heteroaryl ring        containing one to three heteroatoms chosen from O, S, and N,        unsubstituted or optionally substituted by one to three        substituents chosen independently from halogen, CF₃, C₁-C₄        alkyl, hydroxy and C₁-C₄ alkoxy;    -   R′ is hydrogen, C₁-C₆ alkyl, C₂-C4 alkenyl, C₂-C₄ alkynyl, aryl        or aryl-C₁-C₄ alkyl;    -   or a pharmaceutically acceptable salt thereof.

More specifically, the present invention provides a method forinhibiting bone resorption, treating osteoporosis, inhibiting humoralhypercalcemia of malignancy, treating Paget's disease, inhibiting tumormetastasis, inhibiting neoplasia (solid tumor growth), inhibitingangiogenesis including tumor angiogenesis, treating diabeticretinopathy, inhibiting arthritis, psoriasis and periodontal disease,and inhibiting smooth muscle cell migration including restenosis.

The compounds of the invention and the salt thereof can be prepared byand analogy process. Accordingly, the compounds of formula I and thesalts thereof, can be for instance obtained by a process whichcomprises:

-   -   a) reacting a compound of formula II

-   -   where q is zero or 1, y′ is a reactive function, preferably        halogen, and G and X are as defined above, with a compound of        formula III

-   -   where A, Y, R, and R′ are as defined above, thus obtaining a        compound of formula I where B is CONH or CH2—CONH; or    -   b) reacting a compound of formula IV

-   -   where y′ is a reactive function, preferably halogen and G, X and        m are as defined above, with a compound of formula V

-   -   where X′, A, Y, R, and R′ are as defined above, thus obtaining a        compound of formula I where B is —(CH₂)_(m)—X′, wherein X′ and m        are as defined above; or    -   c) reacting a compound of formula VI

-   -   where X, B, A, Y, R, and R′ are as defined above, and Y′ is NH₂,        with a suitable guanilating agent such as        di-Boc-trifyl-guanidine, thus obtaining a compound of formula I        where G is a goanidino group; or    -   d) reacting a compound of formula VI where X, B, A, Y, R, R′ and        Y′ are as defined above, with a benzyl cyanate or a cyanate        salt, as e.g. a ammonium or sodium or potassium salt, thus        obtaining a compound of formula I where G is an urea group; or    -   e) reacting a compound of formula VI where X, B, A, Y, R, R′ and        Y′ are as defined above, with an isocyanate of formula Q′NCO,        where Q′ is a group selected among C1-C6 alkyl, Phenyl,        Phenyl-C1-C4-alkyl, thus obtaining a compound of formula I where        G is a Q′NH(CO)NH— group, in which Q′ is a group selected among        C1-C6 alkyl, Phenyl, Phenyl-C1-C4-alkyl;    -   f) reacting a compound of formula VII

-   -   wherein G, X, B and A, are as defined above and Y″ is a thiol        group, with a compound of formula VIII,

-   -   wherein R and R′ are as defined above, thus obtaining a compound        of formula (I) wherein Y is —S—; or    -   g) reacting a compound of formula IX 1

-   -   wherein G, X, B, A, are as defined above and Y″ is a group Y—H        with a compound of formula X,

-   -   wherein R, R′ and y′ are as defined above, thus obtaining a        compound of formula I;    -   h) hydrolyzing, preferably in acidic conditions, a carboxylic        ester compound of formula I wherein G, X, B, A, Y, R are as        defined above and R′ is different from hydrogen, thus obtaining        a compound of formula I wherein R′ is hydrogen;    -   i) oxidizing with a suitable agent such as NaIO₄ or oxone or        H₂O₂, a compound of formula I wherein G, X, B, A, R and R′ are        as defined above and Y is sulfur, thus obtaining a compound of        formula 1 wherein G, X, B, A, R and R′ are as defined above and        Y is S(O)_(n) wherein n is 1 or 2, i.e. Y is a sulfoxide or        sulfone group;    -   l) cleaving a compound of formula I, wherein G, X, B, A, Y and R        are as defined above and the group R is represented by Wang        (p-bezyloxybenzylalcohol) resin, with TFA in CH₂Cl₂, thus        obtaining a compound of formula I wherein R′ is hydrogen; and,        if desired, salifying a compound of formula (I) and/or, if        desired, converting a salt of a compound of formula (I) into a        free compound and/or, if desired, separating as mixture of        isomers of a compound of formula (I) into the single isomers.

Process-Variants a) to I), Respectively, Can for Instance be Carried outat Follows:

-   -   a) In a typical procedure the acid was added to as large excess        of thionyl chloride (25 equivalents) kept under stirring at        about 0 degree. C. under nitrogen atmosphere, the mixture heated        at about 60 degree. C. for 1 hour, brought to room temperature        and thoroughly evaporated in vacuo. The acid chloride II was        dissolved in DMF and added to a mixture of the intermediate        required (III) (1 equivalent) and triethylamine (1 equivalent)        in DMF or pyridine. The mixture was stirred at room temperature        for 48-72 hours, the solvent removed, the residue taken with        brine and extracted with dichloromethane. The compounds thus        obtained were purified by silica gel flash chromatography        eluting with CH₂Cl₂/MeOH 9:1.    -   b) In a typical procedure compounds of formula IV were added to        a solution of V in solvents like DMF, acetone, in presence of a        base (NaH, K₂CO₃, KHMSA) the temperature varying between room        temperature and reflux, the time of reaction varying between        24-72 hours. The mixture filtered the solvent evaporated and the        residue taken with brine and extracted with dichloromethane or        ethyl acetate. The compounds were purified by silica gel flash        chromatography eluting with CH₂Cl₂/MeOH 9:1 or Petroleum ether        40-60/Ethyl acetate 1:1.    -   c) In a typical procedure the amino derivatives of formula VI        reacted with the guanilating agent, such as        di-Boc-triflyl-guanidine, in dichloromethane in presence of        stechiometric amounts of base such as triethylamine or        diusopropylethylamine, the time of reaction varying between        24-72 hours. The compounds thus obtained did not request further        purification. (FEICHTINGER, K.; ZAPF, C.; SINGS, H. L.; GOODMAN,        M.; J Org 1998, 63 (12), 3804-3805). The protection groups were        removed according to standard procedures, with TFA.    -   d) In a typical procedure the amino derivatives of formula VI        reacted with a cyanate salt, as e.g. a ammonium or sodium or        potassium salt, in solvent such as AcOH, H₂O (Org. Synth. 1963,        IV, 49) PNAS 1993, 90, 6909-6913) the temperature varying        between 50-100 degree. C., the time of reaction varying    -   e)In a typical procedure the amino derivatives of formula VI        reacted with isocyanates in presence of triethylamine refuxing        in solvents such as dichloromethane, acetonitrile, toluene or        dioxane (JMC 1996, 39 (22) 4382-4395; Eur J Med Chem 1997, 32        (10), 795-804.) to give the subtituted ureas, the temperature        varying between room temperature and reflux, the time of        reaction varying between 8-24 hours.    -   f) in a typical procedure to a stirred solution of the acids        VIII (cinnamic or trans-3-(3-pyridyl)acrylic) as ethyl esters or        polymer supported, in dichloromethane kept under vigorous        stirring in nitrogen atmosphere, the amiothiophenols VII (2eq)        and DBU(0.1 equivalent) were added, the mixture was stirred at        room temperature for about 24 hours, the solvent evaporated and        the residue purified by silica gel flash chromatography eluting        with petroleum ether 40-60/ethyl acetate 1:1, to give the        intermediates required.    -   g In a typical procedure compounds of formula X were added to a        solution of IX in solvents like DMF, acetone, in presence of a        base (K₂CO₃, NaH, KHMSA) the temperature varying between room        temperature and reflux, time of reaction varying between 8-24        hours    -   h) The ester compounds of formula I, were hydrolysed by        treatment with a mixture of HCl 4N and ethanol overnight.        Solvents were evaporated and the final compounds, obtained as        hydrochlorides, purified by crystallisation with methanol and        ether.    -   i) The sulfur functions of formula I were oxidised to solfones        with 30% aq H₂O₂ (RAVIKUMAR, K. S.; BEGUE, J.-P.; BONNET-DELPON,        D.; Tetrahedron Lett 1998, 39 (20), 3141-3144.) or with NaIO₄,        in water and methanol, or acetone and water, according to a        standard procedure (BEIER, C.; SCHAUMANN, E.; Synthesis 1997,        (11), 1296-1300; LE MERRER, Y.; FUZIER, M.; DOSBAA, I.;        FOGLIETTI, M. -J.; DEPEZAY, J.-C.; Tetrahedron 1997, 53 (49),        16731-16746). The sulfur functions were oxidised to solfoxides        according to a standard procedure by reacting with oxone in a        mixture methanol/water as a solvent (HINTERBERGER, S.; HOFER,        O.; GREGER, H.; Tetrahedron 1998, 54 (3), 487-496.)    -   l) Compounds of formula 1 linked to the Wang resin were cleaved        as a final step with a mixture trifluoroacetic        acid/dichloromethane, the time of reaction varying between 15-30        minutes.

Also the optional salification of a compound of formula (I) as well asthe conversion of a salt into the free compound and the separation of amixture of isomers into the single isomers may be carried out byconventional methods. For example, the separation of optical isomers maybe carried out by salification with an optically active base or acid andby subsequent fractional crystallization of the diastereoisomeric salts,followed by recovering of the optically active isomeric-acids or,respectively, bases. When in the compound of formula (I), and in theintermediate products thereof, groups are present which need to beprotected before submitting them to the here-above illustratedreactions, they may be protected before the reactions take place andthen deprotected, according to well known methods in organic chemistry.The compounds of formulae (I) and the pharmaceutically acceptable, saltsthereof are herein defined as the “compounds of the present invention”,the “compounds of the invention” and/or the “active principles of thepharmaceutical compositions of the invention”.

For instance, according to process variant a) above, and according theindications herein provided, the compound3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]-phenyl}sulfanyl)-3-(3-pyridinyl)propanoicacid (internal code PNU 277262F) can be provided. In particular compoundPNU 277362F can be synthesized as bis-trifluoroacetate salt, as depictedin scheme 1, according to the procedures reported.

-   -   3-{4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)}--3-(3-pyridinyl)propanoic        acid bis-trifluoroacetate (PNU 277362F)    -   ¹H-NMR (DMSO-d₆): 10.3 (s, 1 H); 9.8 (s, 1 H); 8.5 (m, 2 H);        7.85 (m, 2 H); 7.78 (m, 1 H); 7.7 (d, 2 H) 7.6-7.4 (m, 5 H); 7.3        (d, 2 H), 4.8 (t, 1 H); 2.9 (m, 2 H); Elemental Analysis:        Theoretic: C, 47.06%; H, 3.49%; F, 17.18%; N, 10.55%; S, 4.83%;        Found: C, 44.32%; H, 3.49%; F, 16.70%; N, 9.95%; S, 4.44%

-   -   Z is

-   -   wherein    -   Pol=polymer of Wang resin; DIC=diisopropylcarbodiimide;        DMAP=4-dimethylminopyridine; DBUcat=1,8-diazabicyclo[5,4,0]9        undec-7-ene in catalytic amount; DMF=dimethylformamide;        TFA=trifluoro acetic acid.

Analogously, according to process variant d) above, the compound3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl)-3-(3-pyridinyl)propanoicacid (internal code PNU 515440) is provided.

-   -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)        propanoic acid (PNU 515440)    -   MS; m/z 437 (M+H⁺). ¹H-NMR (400 MHz), .delta. (DMSO-d₆): 2.82        (m, 2 H, CH₂, 4.65 (m, 1 H, CHS), 5.91 (s, 2 H, CONH₂),        7.20-7.70 (m, 9 H, ArH), 7.85 (m, 1 H, ArH), 8.38 (m, 2 H,        pyridine hydrogens), 8.77 (s, 1 H, NHCO), 10.24 (s, 1 H, NHCO).

According to process variant e) above, the compound3-{[4-({3-[(benzylamino)carbonyl])amino]phenyl}sulfanyl)-3—(3-pyridinyl)propanoic acid (internal code PHA 515442E) is provided. The compound PNU515442E can be synthesized as trifluoroacetate salts.

-   -   3-{[4-({3-[(benzylamino)carbonyl])amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)        propanoic acid (PHA 515442E)    -   MS: m/z 527 (M+H⁺). ¹H-NMR (400 MHz), .delta. (DMSO-d₆): 2.97        (m, 2 H, CH₂), 4.29 (d, 2 H, J=5.7, CH₂NH), 4.71 (m, 1 H, CHS),        7.20-7.70 (m, 14 H, ArH) 7.88 (m, 1 H, ArH), 8.53 (m, 2 H,        pyridine hydrogens), 8.77 (s, 1 H, NHCO), 10.27 (s, 1 H, NHCO).

In analogy to process variants a) to l), the following compounds can beobtained:

-   -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfan-        yl)-3-(3-pyridinyl)propanoic acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfan-        yl)-3-(3-pyridinyl)propanoic acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfan-        yl)-3-(3-pyridinyl)propanoic acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(4,5-dihyrdo-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyrdinyl)propanoic        acid;    -   3-[(3-{[4-(4,5-dihyrdo-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyrdinyl)propanoic        acid;    -   3-[(4-{[4-(4,5-dihyrdo-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(3-pyrdinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfanyl)-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfanyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfanyl-3-phenylpropanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfanyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfanyl]-propanoic        acid;    -   3-{2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(4-{[benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{3-[(4-{[benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{4-[(4-{[benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-(3-pyridinyl)propanoic        acid;    -   3-(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-{4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-(3-pyridinyl)propanoic        acid;    -   3-[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-(3-pyridinyl)propanoic        acid;    -   3-{2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-{4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-(3—pyridinyl)propanoic        acid;    -   3-(2-{[3-(4,5-dihydro-1H-imidzaol-2-ylamino)benzoyl]amino}phenoxy—3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[3-(4,5-dihydro-1H-imidzaol-2-ylamino)benzoyl]amino}phenoxy—3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[3-(4,5-dihydro-1H-imidzaol-2-ylamino)benzoyl]amino}phenoxy—3-(3-pyridinyl)propanoic        acid;    -   3-(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-(3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-{2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-phenyl-3-(2-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[3-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-{2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenoxy}-3-phenyl-propanoic        acid;    -   3-{2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-{4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenoxy}—3-phenylpropanoic        acid;    -   3-[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenoxy]-3-phenylpropanoic        acid;    -   3-{2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-{4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenoxy}-3-phenylpropanoic        acid;    -   3-(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)-3-phenylpropanoic        acid;    -   3-(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenoxy)—3-phenylpropanoic        acid;    -   3-phenyl-3-(2-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[4-(2-pyridinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-1-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-1-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-1-3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino]phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino]phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino]phenyl)sulfinyl]propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-(3-pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-(3--pyridinyl)propanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(3-pyridinyl)propanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-(-3-pyridinyl)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-{[2-({-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[3-({-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[4-({-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-pheynylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-pheynylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-pheynylpropanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfinyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfinyl)-3-phenylpropanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfinyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfinyl]-propanoic        acid;    -   3-({3-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({4-[(3-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-{[2-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[3-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[4-({3-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-({2-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(3-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-[(2-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(2-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[3-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[3-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-({2-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({3-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({4-[(4-{[amino(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)--3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)(imino)methyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-{[2-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[3-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-{[4-({4-[(aminocarbonyl)amino]benzoyl}amino)phenyl]sulfonyl}-3-phenylpropanoic        acid;    -   3-({2-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({3-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-({4-[(4-{[(benzylamino)carbonyl]amino}benzoyl)amino]phenyl}sulfonyl)-3-phenylpropanoic        acid;    -   3-[(2-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(4,5-dihydro-1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(2-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(3-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-[(4-{[4-(1H-imidazol-2-ylamino)benzoyl]amino}phenyl)sulfonyl]-3-phenylpropanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(2-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(3-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-phenyl-3-[(4-{[4-(2-pyridinylamino)benzoyl]amino}phenyl)sulfonyl]-propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-phenyl-3-(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenoxy)propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfanyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-phenyl-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfinyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-(3-pyridinyl)-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(2-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(3-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(4-{[3-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(2-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(3-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   3-phenyl-3-[(4-{[4-(1,4,5,6-tetrahydro-2-pyrimidinylamino)benzoyl]amino}phenyl)sulfonyl]propanoic        acid;    -   either as a free acid or a salt thereof, in particular the        hydrochloride or the trifluroacetate.

Having thus described several aspects of at least one embodiment of thisinvention, it is to be appreciated various alterations, modifications,and improvements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure, and are intended to be within the spirit and scope ofthe invention. Accordingly, the foregoing description and drawings areby way of example only.

All of the references cited herein, including published patents andpatent applications are hereby incorporated in their entirety.

What is claimed is: 1-11. (canceled)
 12. A method for treating aproteinuric disorder comprising: administering to a patient in needthereof, a peptide αvβ3 integrin inhibitor comprising an RGD bindingsequence, in an amount effective to treat the proteinuric disorder. 13.The method of claim 12, wherein the proteinuric disorder is a kidneyproteinuric disorder.
 14. The method of claim 13, wherein the kidneyproteinuric disorder is selected from the group consisting of: Diabeticnephropathy, Nephrotic syndromes (i.e. intrinsic renal failure),Nephritic syndromes, Toxic lesions of kidneys, Glomerular diseases, suchas membranous glomerulonephritis, Focal segmental glomerulosclerosis(FSGS), IgA nephropathy, IgM nephropathy, Membranoproliferativeglomerulonephritis, Membranous nephropathy, Minimal change disease,Hypertensive nephrosclerosis, and Interstitial nephritis.
 15. The methodof claim 14, wherein the kidney proteinuric disorder is diabeticnephropathy.
 16. The method of claim 13, wherein the kidney proteinuricdisorder is selected from the group consisting of: Pre-eclampsia,Eclampsia, Collagen vascular diseases, Dehydration, Strenuous exercise,Stress, Benign Orthostatic (postural) proteinuria, Sarcoidosis, Alport'ssyndrome, Diabetes mellitus, Fabry's disease, Infections, Aminoaciduria,Fanconi syndrome, Heavy metal ingestion, Sickle cell disease,Hemoglobinuria, Multiple myeloma, Myoglobinuria, Organ rejection, Ebolahemorrhagic fever, and Nail Patella Syndrome.
 17. The method of claim12, wherein the peptide that contains an RGD binding sequence iscyclo-[Arg-Gly-Asp-D-Phe-Val].
 18. The method of claim 12, wherein thepatient has proteinuria associated with podocytes exhibiting increaseduPAR-induced αvβ3 integrin activation.
 19. The method of claim 18,further comprising detecting increased podocyte αvβ3 integrinactivation.
 20. The method of claim 19, wherein detecting increasedpodocyte αvβ3 integrin activation is performed using an antibody-basedassay.
 21. The method of claim 12, further comprising measuring thepatient's urinary protein prior to and after the administration of theαvβ3 integrin inhibitor, wherein a reduction in the amount of urinaryprotein indicates that the proteinuria is reduced.
 22. The method ofclaim 21, wherein measuring the patient's urinary protein prior toadministration of the peptide comprises detecting 150 mg or more ofprotein in the urine of the subject.
 23. The method of claim 12, whereinthe peptide is administered to the subject intravenously.